WO2008011016A2

WO2008011016A2 - Treating gastroesophageal reflux disease with 5-ht3- and gaba receptor agonists

Info

Publication number: WO2008011016A2
Application number: PCT/US2007/016183
Authority: WO
Inventors: Theodore T. Ashburn
Original assignee: Dynogen Pharmaceuticals, Inc.
Priority date: 2006-07-18
Filing date: 2007-07-17
Publication date: 2008-01-24
Also published as: WO2008011016A3

Abstract

The present invention relates to a method of treating a gastrointestinal motility disorder in subject in need of such treatment comprising coadministering an effective amount of a 5-HT3 receptor agonist or a pharmaceutically acceptable salt, hydrate, or solvate thereof and an effective amount of a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof. Preferably, the subject is a human. The invention is also directed to a method of increasing esophageal motility in a subject in need thereof comprising coadministering to said subject an effective amount of a 5-HT3 receptor agonist or a pharmaceutically acceptable salt, hydrate, or solvate thereof and an effective amount of a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

Description

METHODS FOR TREATING GASTROESOPHAGEAL REFLUX DISEASE

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 60/831,708, filed on July 18, 2006. The entire teachings of the above application is incorporated herein by reference.

BACKGROUND OF THE INVENTION Gastrointestinal (GI) motility regulates the orderly movement of ingested material through the gut to ensure adequate absorption of nutrients, electrolytes and fluids. Appropriate transit through the esophagus, stomach, small intestine and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement and prevent back-flow of GI contents. The normal GI motility pattern can be impaired by a variety of circumstances including disease and surgery.

Disorders of gastrointestinal motility can include, for example, gastroparesis and gastroesophageal reflux disease (GERD). Gastroparesis is the delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea and vomiting. Acute gastroparesis can be caused by, for example, drugs, viral enteritis and hyperglycemia and is typically managed by treating the underlying disease rather than the motility disorder. The most common underlying disease resulting in gastroparesis is diabetes.

GERD is a physical condition in which stomach contents (e.g, stomach acid) reflux or flow back from the stomach into the esophagus. GERD is synonymous with GORD (gastro-osophageal reflux disease). The most common symptom of GERD is a burning sensation or discomfort behind the breastbone or sternum and is referred to as dyspepsia or heartburn. These symptoms can also mimic the symptoms of myocardial infarction or severe angina pectoris. Other symptoms of GERD include dysphagia, odynophagia, hemorrhage, water brash and respiratory manifestations such as asthma, recurrent pneumonia, chronic coughing, intermittent wheezing due to acid aspiration and/or stimulation of the vagus nerve, earache, hoarseness, laryngitis and pharyngitis.

Reflux episodes which result in GERD, can occur both during the daytime (i.e., when the subject is in a waking state) and at nighttime (i.e., when the subject is in a non-waking state). GERD occurring at nighttime is commonly referred to as nocturnal GERD. Nocturnal GERD is distinct from daytime or diurnal GERD not only in the timing of the reflux episode, but in the severity of the damage which occurs as a result of the reflux. More specifically, nocturnal GERD, can be particularly damaging to the pharynx and larynx and a strong association between nocturnal GERD and asthma exists. The increased damage associated with nocturnal GERD is due to a decrease in natural mechanisms which normally help protect against reflux (e.g., saliva production and swallowing), which occur when the patient is sleeping. This decrease leaves the esophagus more vulnerable to damage and can increase microaspiration. In addition, while asleep the body is in the recumbent position, eliminating the effect of gravity, which can clear gastric content from the esophagus. Sleep disorders are also associated with nocturnal GERD resulting in daytime sleepiness and a significant decrease in the overall quality of life.

Chronic GERD subjects the esophagus to ulcer formation or esophagitis and can result in more severe complications such as, esophageal erosions, esophageal obstruction, significant blood loss and perforation of the esophagus. Severe esophageal ulcerations occur in 20-30% of patients over age 65. In addition to esophageal erosions and ulcerations, prolonged exposure of the esophageal mucosa to stomach contents can lead to a condition known as Barrett's Esophagus. Barrett's Esophagus is an esophageal disorder that is characterized by replacement of normal squamous epithelium with abnormal columnar epithelium. This change in tissue character is important clinically not only as an indication of severe reflux, but as an possible precursor of adenocarcinoma of the lower esophagus.

Many factors are believed to contribute to the onset of GERD. A number involve failure of the lower esophageal sphincter (LES) mechanism to function properly. Other factors include, for example, increased transient lower esophageal sphincter relaxations (TLESR) and decreased lower esophageal sphincter (LES) resting pressure (LESP). The LES is a physiologic, non-anatomic area involving the lower 3 centimeters of the esophagus and, like other smooth muscle sphincters in the body (e.g., anal and urinary), the LES is tonically contracted to prevent reflux. In a healthy person the muscle relaxes only during swallowing to allow food to pass and also on average three to four times and hour in a phenomenon known as TLESR. In GERD sufferers, the frequency of TLSER can be much higher, for example, as high as eight or more times an hour and weakness of the LESP allows reflux to occur. Other factors which can contribute to GERD include delayed stomach emptying and ineffective esophageal clearance. The extent and severity of GERD depends not only on the presence of gastroesophageal reflux but on factors including the volume of gastric contents available to reflux, pH, identity and potency of the refluxed material, the interval that the refluxed material remains in the esophagus, salivary volume, frequency of swallows, whether or not the subject is supine or upright and the ability of the esophageal tissue to withstand injury and to repair itself after injury.

Given that there are no safe, durable and effective agents on the market which address the above mentioned upper GI mechanical deficits, a need exists for a new method of treating gastrointestinal motility disorders, such as GERD, which can effectively address the multifactorial etiology of the disorders.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating a gastrointestinal motility disorder in a subject in need of such treatment comprising coadministering an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof. Preferably, the subject is a human.

In one embodiment, the gastrointestinal motility disorder is GERD. More specifically, the GERD is nocturnal GERD.

In another embodiment, the gastrointestinal motility disorder is gastroparesis. The invention is also directed to a method of increasing esophageal motility in a subject in need thereof comprising coadministering to said subject an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another embodiment, the gastrointestinal motility disorder is gastroparesis.

The invention further relates to pharmaceutical compositions for use in therapy or prophylaxis, for example, in the treatment of a gastrointestinal motility disorder in a subject in need of such treatment or for increasing esophageal motility in a subject in need thereof. The pharmaceutical compositions comprise an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another embodiment, the gastrointestinal motility disorder is gastroparesis.

The present invention is also directed to the use of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein for the manufacture of a medicament for use in therapy or prophylaxis, for example, for the treatment of a gastrointestinal motility disorder in a subject in need of treatment or for increasing esophageal motility in a subject in need thereof.

In another embodiment, the gastrointestinal motility disorder is gastroparesis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for treating a gastrointestinal motility disorder in a subject in need of such treatment comprising coadministering an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof. The present invention also provides a method for increasing esophageal motility in a subject in need thereof comprising coadministering an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof. The present invention further relates to pharmaceutical compositions for therapy or prophylaxis, for example for the treatment of a gastrointestinal motility disorder in subject in need of such treatment or for increasing esophageal motility in a subject in need thereof, comprises an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof. The 5-HT₃ receptor agonists and the GABA receptor agonists that can be used in the present invention are described below.

The pharmaceutical compositions of the present invention can optionally contain a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers include pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices. For example, solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers can be aqueous or non-aqueous solvents. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Gastrointestinal motility disorders, as used herein, refers to disorders of the gastrointestinal tract wherein the normal orderly movement of ingested material through the gastrointestinal tract is impaired. Gastrointestinal motility disorders include, for example, gastroparesis and gastroesophageal reflux disease (GERD). Gastroparesis is the delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea and vomiting. Acute gastroparesis can be caused by, for example, drugs, viral enteritis and hyperglycemia and is typically managed by treating the underlying disease rather than the motility disorder. The most common underlying disease resulting in gastroparesis is diabetes.

Gastroesophageal reflux is a physical condition in which stomach contents (e.g, stomach acid, enzymes and bile salts) reflux or flow back from the stomach into the esophagus. Frequent reflux episodes (e.g., two or more times per week) can result in a more severe problem known as gastroesophageal reflux disease (GERD). GERD is synonymous with GORD (gastro-osophageal reflux disease). The most common symptom of GERD is a burning sensation or discomfort behind the breastbone or sternum and is referred to as dyspepsia or heartburn. These symptoms can also mimic the symptoms of myocardial infarction or severe angina pectoris. Other symptoms of GERD include dysphagia, odynophagia, hemorrhage, water brash and respiratory manifestations such as asthma, recurrent pneumonia, chronic coughing, chronic throat clearing, intermittent wheezing due to acid aspiration and/or stimulation of the vagus nerve, earache, hoarseness, sleep disturbances, daytime sleepiness, laryngitis and pharyngitis.

Reflux episodes which result in GERD, can occur both during the daytime (i.e., when the subject is in a waking state) and at nighttime (i.e., when the subject is in a non-waking state). GERD occurring at nighttime is commonly referred to as nocturnal GERD. Nocturnal GERD is distinct from daytime or diurnal GERD not only in the timing of the reflux episode, but in the severity of the damage which occurs as a result of the reflux. More specifically, nocturnal GERD, can be particularly damaging to the pharynx and larynx and a strong association between nocturnal GERD and asthma exists. The increased damage associated with nocturnal GERD is due to a decrease in natural mechanisms which normally help protect against reflux (e.g., saliva production, swallowing and appropriate angle of the gravity vector), which occur when the patient is sleeping. This decreased defence mechanisms leave the esophagus more vulnerable to damage and can increase microaspiration. In addition, while asleep the body is in the recumbent position, eliminating the effect of gravity, which can clear gastric content from the esophagus. Sleep disorders are also associated with nocturnal GERD resulting in daytime sleepiness and a significant decrease in the overall quality of life.

On a chronic basis, GERD subjects the esophagus to ulcer formation or esophagitis and can result in more severe complications such as, esophageal erosion, esophageal obstruction, esophageal strictures, significant blood loss and perforation of the esophagus. Severe esophageal ulcerations occur in 20-30% of patients over age 65. In addition to esophageal erosion and ulceration, prolonged exposure of the esophageal mucosa to stomach contents can lead to a condition known as Barrett's Esophagus. Barrett's Esophagus is an esophageal disorder that is characterized by replacement of normal squamous epithelium with abnormal columnar epithelium. This change in tissue type is important clinically not only as an indication of severe reflux, but also as a precursor to adenocarcinoma of the lower esophagus.

As used herein, "treatment" or "treatment" refers to a reduction in at least one symptom associated with a gastrointestinal motility disorder. For example, the subject having GERD can experience a reduction in any one ore more of the symptoms of dysphagia, odynophagia, hemorrhage, water brash, esophageal erosion, esophageal obstruction and respiratory manifestations such as asthma, recurrent pneumonia, coughing, chronic throat clearing, intermittent wheezing, earache, hoarseness, sleep disturbances, daytime sleepiness, laryngitis and pharyngitis.

As used herein, increasing esophageal motility refers to increasing peristaltic waves and/or LES pressure. Subjects in need of increasing esophageal motility include those suffering from GERD, including nocturnal GERD.

A "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). GABA RECEPTOR AGONIST

GABA receptor (for example, GABA_B receptor) agonists are gamma- aminobutyric acid and compounds that are derived from or based on gamma- aminobutyric acid, i.e. GABA analogs. GABA receptor agonists are either readily available or can be readily synthesized using known methods. Exemplary GABA receptor agonists and their salts include baclofen, gabapentin, pregabalin, PD217,014 and other GABA analogs as described in U.S. Patent No. 4,024,175, U.S. Patent No. 5,563,175, U.S. Patent No. 6,316,638, U.S. Patent No. 6,545,022 Bl, PCT Publication No. WO 93/23383, UK Patent Application GB 2 374 595, Bryans et al., J. Med. Chem. 47:1838-1845 (1998), and Bryans et al., Med. Res. Rev. /9:149-177 (1999), which are incorporated herein by reference.

Other GABA agonists that can be used in the present invention include, but are not limited to, cis-(lS,3R)-( 1 -(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)- 3-methylcyclohexane)acetic acid, lα,3α,5α-(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9-

(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, and (7- '

(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid (Bryans et al., J. Med. Chem. 47:1838-1845 (1998); Bryans et al., Med. Res. Rev. /9:149-177 (1999)).

Exemplary GABA agonists and fused bicyclic or tricyclic amino acid analogs of gabapentin that are useful in the present invention include: 1. Baclofen, represented by the following structure:

or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;

2. Gabapentin, represented by the following structure:

3. Pregabalin, (S)-(3-aminomethyl)-5-methylhexanoic acid, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;

4. GABA analogs according to the following structure as described in U.S. Pat. No. 4,024,175, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,

wherein Ri is hydrogen or a lower alkyl radical and n is 4, 5, or 6;

5. GABA analogs according to the following structure as described in U.S. Pat. No. 5,563,175, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,

H2NC i³H ™"' ""'^■ C i²~~~~CH2COOH Ri wherein Rj is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R₂ is hydrogen or methyl; and R₃ is hydrogen, methyl or carboxyl; 6. Substituted amino acids according to the following structures as described in U.S. Patent No. 6,316,638, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,

wherein Ri to Rio are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; m is an integer of from O to 3; n is an integer from 1 to 2; p is an integer from 1 to 2; q is an integer from 0 to 2; r is an integer from 1 to 2; s is an integer from 1 to 3; t is an integer from 0 to 2; and u is an integer from 0 to 1 ;

7. GABA analogs as disclosed in PCT Publication No. WO 93/23383 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof; 8. GABA analogs as disclosed in Bryans et al. (1998) J. Med. Chem. 41 :1838-1845 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;

9. GABA analogs as disclosed in Bryans et al. (1999) Med. Res. Rev. 19:149-177 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;

10. Amino acid compounds according to the following structure as described in U.S. Application No. 200201 1 1338, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;

wherein Ri and R₂ are independently hydrogen or hydroxy; X is selected from the group consisting of hydroxy and Q*-G- where: G is -O-, -C(O)O- or -NH-;

Q* is a group derived from a linear oligopeptide comprising a first moiety D and further comprising from 1 to 3 amino acids, and wherein said group is cleavable from the amino acid compound under physiological conditions;

D is a GABA analog moiety;

Z is selected from the group consisting of:

(i) a substituted alkyl group containing a moiety which is negatively charged at physiological pH, which moiety is selected from the group consisting of - COOH, -SO₃H, -SO₂H, -P(O)(OR¹⁶XOH), - OP(O)(OR¹⁶XOH), -OSO₃H and the like, and where R¹⁶ is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; and (ii) a group of the formula -M-Q^X|, wherein M is selected from the group consisting of -CHiOC(O)- and -CH₂CH₂C(O)-, and wherein Q^x is a group derived from a linear oligopeptide comprising a first moiety D' and further comprising from 1 to 3 amino acids, and wherein said group is cleavable under physiological conditions; D¹ is a GABA analog moiety; or a pharmaceutically acceptable salt thereof; provided that when X is hydroxy, then Z is a group of formula -M-

Q^x>;

1 1. Cyclic amino acid compounds as disclosed in PCT Publication No. WO 99/08670 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;

12. Cyclic amino acids according to the following structures as disclosed in

PCT Publication No. WO99/21824, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,

wherein R is hydrogen or a lower alkyl; R| to R₁₄ are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl,- CO₂H₅-CO₂Ri

-ORi₅ wherein Rj₅ is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and Ri to Re are not simultaneously hydrogen;

13. Bicyclic amino acids according to the following structures wherein n is an integer as disclosed in U.S. Patent Application Serial No. 60/160725, including those disclosed as having high activity as measured in a radioligand binding assay using [3H]gabapentin and the α2δ subunit derived from porcine brain tissue, or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof,

14. Bicyclic amino acid analogs according to the following structures as disclosed in UK Patent Application GB 2 374 595 and acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof,

(V) (VI) (VII) (VIII)

(IX) (X) (XI) (XII)

(XVIII) (XIX) (XX) (XXI)

(XXl) (XXII) (XXIII) (XXIV) wherein Rl and R2 are independently selected from H, straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from 3-6 carbons atoms, phenyl and benzyl, subject to the proviso that, except in the case of a tricyclooctane compound of formula (XVII), Rl and R2 are not simultaneously hyrogen; and 15. Gamma-aminobutyric acid and its analogs

In a preferred embodiment, the GABA receptor agonists are selected from the group consisting of baclofen (both enantiomers), XP- 19986, gabapentin, pregabalin, PD217.014, cis-(lS,3R)-( l-(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3-methylcyclohexane)acetic acid, lα,3α,5α-(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9- (aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, (7-

(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist is baclofen. 5-HT₃ RECEPTOR AGONISTS

The neurotransmitter serotonin was first discovered in 1948 and has been subsequently the subject of substantial scientific research. Serotonin, also referred to as 5-hydroxytryptamine (5-HT), acts both centrally and peripherally on discrete 5- HT receptors. Currently, at least fourteen subtypes of serotonin receptors are recognized and delineated into seven families, 5-HTi through 5-HT₇. These subtypes share sequence homology and display some similarities in their specificity for particular ligands. While these receptors all bind serotonin, they initiate different signaling pathways to perform different functions. For example, serotonin is known to activate submucosal intrinsic nerves via 5-HTi p and 5-HT4 receptors, resulting in, for example, the initiation of peristaltic and secretory reflexes. However, serotonin is also known to activate extrinsic nerves via 5-HT₃ receptors, resulting in, for example, the initiation of bowel sensations, nausea, bloating and pain. A review of the nomenclature and classification of the 5-HT receptors can be found in Neuropharm., 33: 261-273 (1994) and Pharm. Rev., 45:157-203 (1994).

5-HT₃ receptors are ligand-gated ion channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization have been found to affect the regulation of visceral pain and colonic transit. Antagonism of the 5-HT₃ receptors has the potential to influence sensory and motor function in the gut.

As used herein, 5-HT₃ receptor refers to naturally occurring 5-HT₃ receptors (e.g., mammalian 5-HT₃ receptors (e.g., human (Homo sapiens) 5-HT₃ receptors, murine (e.g., rat, mouse) 5-HT₃ receptors, feline (e.g., cat) 5-HT₃ receptors)) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring 5-HT₃ receptor (e.g., recombinant proteins). The term includes naturally occurring variants, such as polymorphic or allelic variants and splice variants.

As used herein, the term a 5-HT₃ receptor agonist refers to a substance (e.g., a molecule, a compound) which promotes (induces or enhances) at least one function characteristic of a 5-HT₃ receptor. In one embodiment, the 5-HT₃ receptor agonist binds the 5-HT₃ receptor (i.e., is a 5-HT₃ receptor agonist). In certain embodiments, the agonist is a partial agonist. Partial agonist, as used herein, refers to an agonist which no matter how high of a concentration is used, is unable to produce maximal activation of the 5-HT₃ receptor. A 5-HT₃ receptor agonist (e.g., a 5-HT₃ receptor agonist) can be identified and activity assessed by any suitable method. For example, the binding affinity of a 5-HT₃ receptor agonist to the 5-HT₃ receptor can be determined by the ability of the compounds to displace [³H]granisetron from rat cortical membranes (Cappelli et al, J. Med. Chem., 42(9): 1556-1575 (1999)). In addition, the agonist activity of the compounds can be assessed in vitro on, for example, the 5-HT₃ receptor-dependent [^l4C]guanidinium uptake in NG 108-15 cells as described in Cappelli et al.

In one embodiment of the present invention, 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA_B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein). Preferably, the GABA receptor agonists are selected from the group consisting of baclofen (both enatiomers), XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l -aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen.

In a particular embodiment, the 5-HT₃ receptor agonist is a thieno[3,2- bjpyridine derivatives such as those described in U.S. Patent No. 5,352,685, the entire content of which is incorporated herein by reference.

In a specific embodiment, the 5-HT₃ receptor agonist activity is represented by Structural Formula I:

wherein:

Ri represents hydrogen, a Ci-Ce alkyl group, a C₂-Ce alkenyl group, a

C₂-C6 alkynyl group, a C3-C8 cycloalkyl group, a C6-C12 aryl group or a C7-C18 aralkyl group;

R₂ represents hydrogen, a Ci-C₆ alkyl group, halogen, hydroxyl, a Ci-

Cβ alkoxy group, amino, a C_J-C_G alkylamino group, nitro, mercapto or a Ci-Cg alkylthio group;

Y represents -O- or ^N wherein R₃ represents hydrogen or a Ci -C^ alkyl group; and A is represented by

wherein: n is an integer from 1 to about 4; R₄ represents hydrogen, a Ci-C₆ alkyl group, a C₃-Cs cycloalkyl group or a C₇-Ci_S aralkyl group or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide derivative thereof. The 5-HT₃ agonist represented by the Structural Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA_B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 therein). Preferably, the GABA receptor agonists are selected from the group consisting of baclofen (both enatiomers), XP- 19986, gabapentin, pregabalin, PD214,017, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen. It is understood that when Rj of Structural Formula I is hydrogen, compounds having the tautomeric form represented by Structural Formula IA are included within the definition of Structural Formula I.

Likewise, it is understood that Structural Formula IA includes the tautomeric form represented by Structural Formula I when R| is hydrogen. In one embodiment, the 5-HT₃ receptor agonist represented by Structural

Formula I can be N-oxide derivatives.

In another embodiment of Structural Formula I, Y represents -O- or

H

I

^N ; Ri represents hydrogen, a Ci-Cβ alkyl group, a Ce-Ci₂ aryl group, or a C₇-

Ci8 aralkyl group; R₂ represents hydrogen, a Ci-Ce alkyl group or halogen; and A is represented by

wherein: n is 2 or 3; and R4 represents a Ci-C₆ alkyl group.

In a particular embodiment, the 5-HT₃ receptor agonist is represented by

Structural Formula I, wherein Ri represents hydrogen or a C₁-C3 alkyl group; R₂ represents hydrogen, a C1-C₃ alkyl group or halogen; R₃ represents hydrogen; R4 represents a C₁-C₃ alkyl group and n is an integer of 2 or 3.

In a particularly preferred embodiment, the 5-HT₃ receptor agonist is represented by structural Structural Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof. The 5-HT₃ agonist represented by the Structural Formula V or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA_B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 therein). Preferably, the GABA receptor agonists are selected from the group consisting of baclofen (both enatiomers), XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3-methylcyclohexane)acetic acid, cis- (lR,3S)-(l-(aminomethyl)-3-methylcyclohexane)acetic acid, lα,3α,5α-(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9- (aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-

(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen.

In a particular embodiment, the compound represented by Structural Formula

V is an N-oxide derivative.

In a particularly preferred embodiment, the compound of Structural Formula

V has the (R) configuration at the chiral carbon atom which is designated with an asterisk (*). The chemical name of the compound set forth in Structural Formula V having the (R) configuration at the designated chiral carbon is: (R)-N-I- azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide. When the compound is in the form of the monohydrochloride, it is known as MKC- 733, Dynogen Development Program (DDP733) and pumosetrag (CAS Number: 194093-42-0). When the compound of Structural Formula V has the (S) configuration at the chiral carbon atom designated with an asterisk (*), the chemical name is (S)-N-I -azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine- 6-carboxamide.

It is understood that Structural Formula V includes the tautomeric form depicted by Structural Formula VA:

Likewise, it is understood that Structural Formula VA includes the tautomeric form represented by Structural Formula V. For example, when Structural Formula V has the (R) configuration at the designated chiral carbon the compound is referred to as: (R)-N-I- azabicyclo[2.2.2]pct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide which is understood to include the tautomeric form: (R)-N-I -azabicyclo[2.2.2]oct- 3-yl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide.

Likewise, when Structural Formula VA has the (R) configuration at the designated chiral carbon the compound is referred to as: (R)-N-I- azabicyclo[2.2.2]oct-3-yl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide, which is understood to include the tautomeric form: (R)-N- 1-azabicyclo [2.2.2]oct-3-yl-4,7- dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide.

In another embodiment, the 5-HT₃ receptor agonist is a condensed thiazole derivative such as those described in U.S. Patent No. 5,565,479, the entire content of which is incorporated herein by reference.

In a particular embodiment, the 5-HT₃ receptor agonist is represented by Structural Formula VI or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof:

wherein:

R represents hydrogen, halogen, hydroxyl, a Ci-Cβ alkoxy group, carboxy, a Ci-C_δ alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;

I A )

^^ is a phenyl ring or a naphthalene ring; L is a direct bond or a C)-C_O alkylene group; Li and L₂ are defined so that one is a direct bond and the other is: a) a Cj-Cβ alkylene group optionally containing an interrupting oxygen or sulfur atom therein; b) an oxygen atom or sulfur atom; or c) a Ci-Ce alkenylene group; Im represents a group having the formula:

wherein:

Ri-Rs are the same or different each representing hydrogen or a Ci-C₆ alkyl group. In a further embodiment, the compound according to Structural Formula VI,

^^ is a phenyl ring, Li is a direct bond and L₂ is an alkylene group or alkenylene group.

The 5-HT₃ agonist represented by Structural Formula VI or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA_B receptor) agonist in the section entitled

"GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4,

5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 therein). Preferably, the GABA receptor agonists are selected from the group consisting of baclofen, XP-19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3-methylcyclohexane)acetic acid, lα,3α,5α-(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9-

(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-

(aminomethyl)bicyclo[2.2. l]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen. In a particularly preferred embodiment, the 5-HT₃ receptor agonist is represented by Structural Formula VII:

or a pharmaceutically acceptable salt, solvate, or hydrate thereof. This compound is commonly referred to in the art as YM 31636. The chemical name of the compound set forth in Structural Formula VII is: 2-(lH-imidazol-4-ylmethyl)-8H-indeno[l,2- d]thiazole. The 5-HT₃ agonist represented by Structural Formula VII or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA_B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein). Preferably, the GABA receptor agonists are selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-( 1R,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen.

In another embodiment of the present invention, the 5-HT₃ receptor agonist is m-chlorophenylbiguanide (mCPBG) represented by the following structural formula:

The 5-HT₃ agonist mCPBG or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA_B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein). Preferably, the GABA receptor agonists are selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(l S,3R)-( 1-

(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3. l]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen. MODES OF ADMINISTRATION

The compounds for use in the methods or compositions of the invention can be formulated for oral, transdermal, sublingual, buccal, parenteral, rectal, intranasal, intrabronchial or intrapulmonary administration. For oral administration the compounds can be of the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets can be coated using suitable methods. Liquid preparation for oral administration can be in the form of solutions, syrups or suspensions. The liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).

For buccal administration, the compounds for use in the methods or compositions of the invention can be in the form of tablets or lozenges formulated in a conventional manner.

For parenteral administration, the compounds for use in the methods or compositions of the invention can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or infusion (e.g., continuous infusion).

Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents can be used.

For rectal administration, the compounds for use in the methods or compositions of the invention can be in the form of suppositories.

For sublingual administration, tablets can be formulated in conventional manner. For intranasal, intrabronchial or intrapulmonary administration, conventional formulations can be employed.

Further, the compounds for use in the methods or compositions of the invention can be formulated in a sustained release preparation. For example, the compounds can be formulated with a suitable polymer or hydrophobic material which provides sustained and/or controlled release properties to the active agent compound. As such, the compounds for use the method of the invention can be administered in the form of microparticles for example, by injection or in the form of wafers or discs by implantation. Additional dosage forms suitable for use in the methods or compositions of the invention include dosage forms as described in U.S. Pat. No. 6,340,475, U.S. Pat. No. 6,488,962, U.S. Pat. No. 6,451,808, U.S. Pat. No. 6,340,475, U.S. Pat. No. 5,972,389, U.S. Pat. No. 5,582,837, and U.S. Pat. No. 5,007,790. Additional dosage forms include those described in U.S. Pat. Application No. 20030147952, U.S. Pat. Application No. 20030104062, U.S. Pat. Application No. 20030104053, U.S. Pat. Application No. 20030044466, U.S. Pat. Application No. 20030039688, and U.S. Pat. Application No. 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Patent Application WO 03/35041 , PCT Patent Application WO 03/35040, PCT Patent Application WO 03/35029, PCT Patent Application WO 03/35177, PCT Patent Application WO 03/35039, PCT Patent Application WO 02/96404, PCT Patent Application WO 02/32416, PCT Patent Application WO 01/97783, PCT Patent Application WO 01/56544, PCT Patent Application WO 01/32217, PCT Patent Application WO 98/55107, PCT Patent Application WO 98/1 1879, PCT Patent Application WO 97/47285, PCT Patent Application WO 93/18755, and PCT Patent Application WO 90/11757. In one embodiment, the dosage forms of the present invention include pharmaceutical tablets for oral administration as described in U.S. Patent Application No. 20030104053. The dosage forms of this invention include dosage forms in which the same drug is used in both the immediate-release and the prolonged-release portions as well as those in which one drug is formulated for immediate release and another drug, different from the first, for prolonged release. This invention is particularly directed to dosage forms in which the immediate- release drug is at most sparingly soluble in water, i.e., either sparingly soluble or insoluble in water, while the prolonged-release drug can be of any level of solubility. More particularly, the prolonged-release portion of the dosage form can be a dosage form that delivers drug to the digestive system continuously over a period of time of at least an hour and preferably several hours and the drug is formulated as described in U.S. Patent Application No. 20030104053. In said embodiment, the immediate-release portion of the dosage form is either a coating applied or deposited over the entire surface of a unitary prolonged-release core, or a single layer of a tablet constructed in two or more layers, one of the other layers of which is the prolonged-released portion and is formulated as described in U.S. Patent Application No. 20030104053.

In another embodiment of the invention, the supporting matrix in controlled - release tablets or controlled release portions of tablets is a material that swells upon contact with gastric fluid to a size that is large enough to promote retention in the stomach while the subject is in the digestive state, which is also referred to as the postprandial or "fed" mode. This is one of two modes of activity of the stomach that differ by their distinctive patterns of gastroduodenal motor activity. The "fed" mode is induced by food ingestion and begins with a rapid and profound change in the motor pattern of the upper gastrointestinal (GI) tract. The change consists of a reduction in the amplitude of the contractions that the stomach undergoes and a reduction in the pyloric opening to a partially closed state. The result is a sieving process that allows liquids and small particles to pass through the partially open pylorus while indigestible particles that are larger than the pylorus are retropelled and retained in the stomach. This process causes the stomach to retain particles that are greater than about 1 cm in size for about 4 to 6 hours. The controlled-release matrix in these embodiments of the invention is therefore selected as one that swells to a size large enough to be retropelled and thereby retained in the stomach, causing the prolonged release of the drug to occur in the stomach rather than in the intestines. Disclosures of oral dosage forms that swell to sizes that will prolong the residence time in the stomach are found in U.S. Pat. No. 6,448,962, U.S. Pat. No. 6,340,475, U.S. Pat. No. 5,007,790, U.S. Pat. No. 5,582,837, U.S. Pat. No. 5,972,389, PCT Patent Application WO 98/55107, U.S. Patent Application No. 20010018707, U.S. Patent Application No. 20020051820, U.S. Patent Application No. 20030029688, U.S. Patent Application No. 20030044466, U.S. Patent Application No. 20030104062, U.S. Patent Application No. 20030147952, U.S. Patent Application No. 20030104053, and PCT Patent Application WO 96/26718. In particular, gastric retained dosage formulations for specific drugs have also been described, for example a gastric retained dosage formulation for gabapentin is disclosed in PCT Patent Application WO 03/035040.

COADMINISTRATION When the methods of the invention include coadministration, coadministration refers to administration of an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof. Coadministration encompasses administration of the 5-HT3 receptor agonist and the GABA receptor agonist in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of the 5-HT₃ receptor agonist and the GABA receptor agonist, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either order. When coadministration involves the separate administration of the 5-HT3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate derivative thereof and the GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate derivative thereof, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration, which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, the 5-HT₃ receptor agonist and the GABA receptor agonist can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other. Staggered release of agents can be accomplished in single composition using any suitable formulation technique such as those described above. For example, a variety of coating thicknesses and/or different coating agents can provide staggered release of agents from a single composition, and release at a desired location in the upper GI tract.

When the coadministration comprises administration of the 5-HT₃ receptor agonist and the GABA receptor agonist as separate compositions, either at the same time or sequentially, the separate compositions can be formulated to achieve the desired release profile. For example, the separate compositions can be formulated to release primarily in the duodenum rather than in the acidic environment of the stomach. A variety of formulation techniques such as gastric retention techniques, coating techniques and the use of suitable excipients and/or carriers can be utilized to achieve the desired release.

An additional therapeutic agent can be used in the method of treating a gastrointestinal motility disorder or increasing esophageal motility and in compositions of the invention described herein. Additional therapeutic agents suitable for use in the method of treating GERD and in compositions of the invention can be, but are not limited to, antacids, for example, TUMS^® and ROLAIDS^®. Generally, the additional therapeutic agent will be one that is useful for treating the disorder of interest. Preferably, the additional therapeutic agent does not diminish the effects of the therapy and/or potentiates the effects of the primary administration.

DOSING An "effective amount" refers to an amount effective to obtain therapeutic or prophylactic effect without including unacceptable side effects. In accordance with the present invention, therapeutic effect refers to inhibiting development of, or to alleviating the existing symptoms of the gastrointestinal motility disorder in the subject being treated or increaseing esopheal motility in a subject in need thereof. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and ED_5O (the dose that provides 50% of the maximal response and/or is therapeutically effective in 50% of the population). The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. The exact formulation, route of administration, and dosage is chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain desired therapeutic effects. In addition to the patient's condition and the mode of administration, the dose administered would depend on the severity of the patient's symptoms and the patient's sex, age and weight, the current medical condition of the patient and the nature of the gastrointestinal motility disorder being treated. In accordance with the present invention, an "effective amount" of a 5-HT₃ receptor agonist encompasses alone or in combination with a GABA receptor agonist to achieve therapeutic effect. Likewise, an "effective amount" of a GABA receptor agonist encompasses an amount effective to achieve therapeutic effect alone or in combination with a 5-HT₃ receptor agonist. When the 5-HT₃ receptor agonist or GABA receptor agonist is administered in an amount which alone does not provide a therapeutic effect, the amount is referred herein as a "sub-therapeutic" dose.

In certain embodiments, coadminstration of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect resulting from separate administration of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof alone.

An advantage of the synergistic effect of the combination therapy is the ability to use less of each agent than is needed when each is administered alone. As such, undesirable side effects associated with the agents are reduced (partially or completely). A reduction in side effects can result in increased patient compliance over current treatments.

The presence of a synergistic effect can be determined using suitable methods for assessing drug interaction. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.

As used herein, continuous dosing refers to the chronic administration of a selected active agent.

As used herein, as-needed dosing, also known as "pro re nata" "prn" dosing, and "on demand" dosing or administration is meant the administration of a therapeutically effective dose of the compound(s) at some time prior to commencement of an activity wherein suppression of the gastrointestinal motility disorder would be desirable. Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation. For example, the combination therapy can be administered about one hour before sleep to treat nocturnal GERD.

In a particular embodiment, drug administration or dosing is on an as-needed basis, and does not involve chronic drug administration. With an immediate release dosage form, as-needed administration can involve drug administration immediately prior to commencement of an activity wherein suppression of the symptoms of the GERD would be desirable, but will generally be in the range of from about 0 minutes to about 10 hours prior to such an activity, preferably in the range of from about 0 minutes to about 5 hours prior to such an activity, most preferably in the range of from about 0 minutes to about 3 hours prior to such an activity.

A suitable dose per day for each of the 5-HT₃ receptor agonist or the GABA receptor agonist for administration can be in .the range of from about 1 ng to about 10,000 mg, about 5 ng to about 9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg, about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50 ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng to about 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about 4,500 mg, about 500 ng to about 4,000 mg, about 1 μg to about 3,500 mg, about 5 μg to about 3,000 mg, about 10 μg to about 2,600 mg, about 20 μg to about 2,575 mg, about 30 μg to about 2,550 mg, about 40 μg to about 2,500 mg, about 50 μg to about 2,475 mg, about 100 μg to about 2,450 mg, about 200 μg to about 2,425 mg, about 300 μg to about 2,000, about 400 μg to about 1,175 mg, about 500 μg to about 1,150 mg, about .5 mg to about 1,125 mg, about 1 mg to about 1,100 mg, about 1.25 mg to about 1,075 mg, about 1.5 mg to about 1,050 mg, about 2.0 mg to about 1,025 mg, about 2.5 mg to about 1,000 mg, about 3.0 mg to about 975 mg, about 3.5 mg to about 950 mg, about 4.0 mg to about 925 mg, about 4.5 mg to about 900 mg, about 5 mg to about 875 mg, about 10 mg to about 850 mg, about 20 mg to about 825 mg, about 30 mg to about 800 mg, about 40 mg to about 775 mg, about 50 mg to about 750 mg, about 100 mg to about 725 mg, about 200 mg to about 700 mg, about 300 mg to about 675 mg, about 400 mg to about 650 mg, about 500 mg, or about 525 mg to about 625 mg.

Other suitable doses per day for each of the 5-HT₃ receptor agonist or the GABA receptor agonist for administration include doses of about or greater than 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng, about 300 ng, about 400 ng, about 500 ng, about 1 μg, about 5 μg, about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg (0.5 mg), about 1 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1 100 mg, about 1 125 mg, about 1 150 mg, about 1 175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 3,000 mg, about 3,500 mg, about4,000 mg, about4,500 mg, about 5,000 mg, about 5,500 mg, about 6,000 mg, about 6,500 mg, about 7,000 mg, about 7,500 mg, about 8,000 mg, about 8,500 mg, about 9,000 mg, or about 9,500 mg.

In a particular embodiment, a suitable dose of 5-HT₃ receptor agonist can be in the range of from about 0.1 mg to about 100 mg per day, such as from about 0.5 mg to about 50 mg, for example, from about 1 mg to about 25 mg per day. The dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different.

In a particular embodiment, the suitable dose of the GABA receptor agonist can be in the range of from about 50 mg to about 5000 mg per day, such as from about 100 mg to about 2500 mg, for example, from about 500 mg to about 2000 mg per day.

It is understood that the dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different.

It is understood that a per day dose of the compounds of the combination can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days etc. The compounds for use in the method of the invention can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. Suitable amounts for use in preparation of a unit dosage form are described above for both the 5-HT₃ receptor agonist and the GABA receptor agonist. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

The invention further includes a kit for treating a gastrointestinal motility disorder or for increasing esophageal motility. The kit comprises a 5-HTj receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and instructions for use with the GABA receptor agonist according to the method of the invention and optionally a device for administering the compounds of the invention. In a particular embodiment, the 5-HT₃ receptor agonist is present in the kit in a subtherapeutic dose. In another particular embodiment, the GABA receptor agonist is present in the kit in a sub-therapeutic dose. In another embodiment, the instructions direct administration of the GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof in a sub-therapeutic dose. In another embodiment, the instructions direct administration of the compound having 5-HT₃ receptor agonist activity in a sub-therapeutic dose.

Compounds can be in separate dosage forms or combined in a single dosage form. In other embodiments of the kits, the instructional insert further includes instructions for administration with an additional therapeutic agent as described herein.

It is understood that in practicing the method or using a kit of the present invention that administration encompasses administration by different individuals (e.g., the subject, physicians or other medical professionals) administering the same or different compounds.

As used herein, the term pharmaceutically acceptable salt refers to a salt of a compound_. to be administered prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.

The active compounds disclosed can be prepared in the form of their hydrates, such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like and as solvates.

It is understood that suitable 5-HT₃ receptor agonists, GABA receptor (for example GABA_B receptor) agonist can be identified, for example, by screening libraries or collections of molecules using suitable methods. Another source for the compounds of interest are combinatorial libraries which can comprise many structurally distinct molecular species. Combinatorial libraries can be used to identify lead compounds or to optimize a previously identified lead. Such libraries can be manufactured by well-known methods of combinatorial chemistry and screened by suitable methods.

An "aliphatic group" is non-aromatic, consists solely of carbon and hydrogen and can optionally contain one or more units of unsaturation, e.g., double and/or triple bonds and/or one or more suitable substituents. An aliphatic group can be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about 1 and about 12 carbon atoms, more typically between about 1 and about 6 carbon atoms. When cyclic, an aliphatic group typically contains between about 3 and about 10 carbon atoms, more typically between about 3 and about 8 carbon atoms, e.g., a cyclopropyl group, cyclohexyl group, cyclooctyl group etc. Aliphatic groups can be alkyl groups (i.e., completely saturated aliphatic groups, e.g., a C]-Ce alkyl group, such as a methyl group, propyl group, hexyl group, etc.), alkenyl groups (i.e., aliphatic groups having one or more between about 3 and about 8 carbon atoms, e.g., a cyclopropyl group, cyclohexyl group, cyclooctyl group etc. Aliphatic groups can be alkyl groups (i.e., completely saturated aliphatic groups, e.g., a Ci-Ce alkyl group, such as a methyl group, propyl group, hexyl group, etc.), alkenyl groups (i.e., aliphatic groups having one or more carbon-carbon double bonds, e.g., C₂-Ce alkenyl group, such as a vinyl group, butenyl group, hexenyl group etc.) or alkynyl groups (i.e., aliphatic groups having one or more carbon-carbon triple bonds, e.g., a C₂-C₆ alkynyl group, such as an ethynyl group, butynyl group, hexenyl group, etc.)- Aliphatic groups can optionally be substituted with a designated number of substituents, as described herein. Alkylene group as used herein refers to the triatomic group having one carbon atom and two attached hydrogens (-CH₂-Or =CH₂) groups such as Ci-Ce alkylene, for example, methylene, ethylene, methylmethylene, trimethylene, 1- methyl ethylene etc.

Alkenylene group as used herein refers to the diatomic group having one carbon atom and one attached hydrogen. Suitable alkenylene groups include C₂-C_O alkenylene groups such as vinylene, propenylene, 1-methylvinylene, etc.

An "aromatic group" (also referred to as an "aryl group") as used herein includes carbocyclic aromatic groups, heterocyclic aromatic groups (also referred to as "heteroaryl") and fused polycyclic aromatic ring systems as defined herein which can be optionally substituted with a suitable substituent.

A "carbocyclic aromatic group" is an aromatic ring of 5 to 14 carbons atoms, and includes a carbocyclic aromatic group fused with a 5-or 6-membered cycloalkyl group such as indan. Examples of carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, e.g., 1-naphthyl and 2-naphthyl; anthracenyl, e.g., 1- anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, e.g., 9-fluorenonyl, indanyl and the like. A carbocyclic aromatic group is optionally substituted with a designated number of substituents, described below.

A "heterocyclic aromatic group" (or "heteroaryl") is a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S. Examples of heteroaryl include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as α-pyridyl), 3-pyridyl (also referred to as β-pyridyl) and 4-pyridyl (also referred to as γ-pyridyl); thienyl, e.g., 2- oxazoyl, 4-oxazoyl and 5- oxazoyl; isoxazoyl; pyrrolyl; pyridazinyl; pyrazinyl and the like. Heterocyclic aromatic (or heteroaryl) as defined above can be optionally substituted with a designated number of substituents, as described below for aromatic groups. A "fused polycyclic aromatic" ring system is a carbocyclic aromatic group or heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring. Examples include, quinolinyl and isoquinolinyl, e.g, 2-quinolinyl, 3-quinolinyl, 4- quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl, 1- isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7- isoquinolinyl and 8-isoquinolinyl; benzofuranyl, e.g., 2 -benzofuranyl and 3- benzofuranyl; dibenzofuranyl, e.g., 2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, e.g., 2-benzothienyl and 3-benzothienyl; indolyl, e.g., 2-indolyl and 3-indolyl; benzothiazolyl, e.g., 2-benzothiazolyl; benzooxazolyl, e.g., 2- benzooxazolyl; benzimidazolyl, e.g., 2-benzoimidazolyl; isoindolyl, e.g., 1- isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl; thianaphthenyl and the like. Fused polycyclic aromatic ring systems can optionally be substituted with a designated number of substituents, as described herein.

An "aralkyl group" (arylalkyl) is an alkyl group substituted with an aromatic group, preferably a phenyl group. A preferred aralkyl group is a benzyl group. Suitable aromatic groups are described herein and suitable alkyl groups are described herein. An aralkyl group can optionally be substituted, and suitable substituents for an aralkyl group (substituted on the aryl, alkyl or both moieties) are described herein.

As used herein, many moieties or groups are referred to as being either "substituted or unsubstituted". When a moiety is referred to as substituted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted. For example, the substitutable group can be a hydrogen atom which is replaced with a group other than hydrogen (i.e., a substituent group). Multiple substituent groups can be present. When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites on the group or moiety. Such means for substitution are well-known in the art. For purposes of exemplification, which should not be construed as limiting the scope of this invention, some examples of groups that are substituents are: alkyl groups (e.g., Ci-C₆ alkyl groups) which can also be substituted, such as CF3), alkoxy groups (e.g., Ci-C₆ alkoxy, such as a methoxy group, propoxy group, hexyloxy group etc.) which can be substituted, such as OCF₃), a halogen or halo group (F, Cl, Br, I), hydroxy, nitro, thio (also referred to as mercapto), akylthio (e.g., Ci-C₆ alkylthio), oxo, -CN, -COH, -COOH, amino, N- alkylamino (e.g., Ci-C₆ alkylamino) or N,N-dialkylamino (in which the alkyl groups can also be substituted), esters (-C(O)-OR, where R can be a group such as alkyl, aryl, etc., which can be substituted), aryl (most preferred is phenyl, which can be substituted) and arylalkyl (which can be substituted).

N-oxide refers a functionality wherein an oxygen atom is bonded to the nitrogen of a tertiary amine.

Protected hydroxy 1 refers to a hydroxyl group in which the hydrogen atom of the hydroxy group has been replaced with a suitable hydroxy protecting group. Suitable hydroxy protecting groups include but are not limited to, for example, benzyl, tert-butyl, acetyl, trifluoroacetyl, benzoyl and benzyloxycarbonyl.

STEREOCHEMISTRY

Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

When compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes either or both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization (See, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC

Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer. For example, the "R" forms of the compounds are substantially free from the "S" forms of the compounds and are, thus, in enantiomeric excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free of "R" forms of the compounds and are, thus, in enantiomeric excess of the "R" forms. Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%. For example, the enantiomeric excess can be about 60% or more, such as about 70% or more, for example about 80% or more, such as about 90% or more. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%. In a more particular embodiment, the enantiomeric excess of the compounds is at least about 95%, such as at least about 97.5%, for example, at least about 99% enantiomeric excess.

When a compound of the present invention has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers which are not mirror-images (e.g., (S,S) and (R₅S)) are diastereomers. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of such compounds and mixtures thereof.

The invention will now be described more specifically with the examples.

EXAMPLE 1 EFFECT OF MKC-733 AND BACLOFEN IN SUPPRESSION OF LOWER ESOPHAGEAL SPHINCTER RELAXATION

Pharmacological Methods. The efficacy of the combination therapy can be assessed through monitoring of the patient's symptoms. For example, an improvement in symptoms such as, hoarseness, cough, heartburn, asthma and overall quality of life can be assessed without the need for invasive testing.

In addition, patients receiving the combination therapy can be subjected to gastroesophageal testing, for example, esophageal manometry followed by ambulatory gastroesophageal pH monitoring. This type of gastoesophageal testing can be conducted according to established protocols such as those found in Fackler et al, Gastroenterology 122(3): 625-632 (2002).

Esophageal Manometry. Briefly, esophageal manometry is used to locate the LES of all study participants using the station pull-through technique. LES pressure and location are recorded by a computerized motility system such as Synectics Gastrosoft Polygram, Milwaukee, WI.

Ambulatory Gastroesophageal pH Monitoring. Twenty-four hour pH level monitoring is then conducted in all study participants. Monitoring is performed with 2.1 mm monocrystalline pH catheters with 2 antimony electrodes separated by 15 cm (Medtronic Functional Diagnostics Zinetics, Inc., Salt lake City, UT). The reference electrode is internalized. The pH electrodes are calibrated at 37 EC in buffer solutions of pH 7 and pH 1 (Fisher Scientific, Fairlawn, NJ) before each study. After calibration, the pH probe apparatus is passed nasally and positioned such that the distal electrode is in the gastric fundus, 10 cm below the proximal border of the lower esophageal sphincter. The probe apparatus is secured to the nose and cheek to prevent dislodgment. The pH electrodes are connected to a portable digital data recorder (Digitrapper Mark III Gold; Synectics) worn around the waist, which stores pH data samples every 4 seconds for up to 24 hours. Patients then return home with instructions to keep a diary recording meal times, time of lying down for sleep, and time of rising in the morning. Patients are encouraged to perform their normal daily activities, consume their customary diet without restrictions, and avoid sleeping for short periods during the day. They return the following day after a minimum of 18 hours to have their probes removed and their diaries reviewed.

Additional pH monitoring following onset of combination therapy is conducted at predetermined time points and the data compared and analyzed to determine the effectiveness among combination therapies and the effectiveness of combination therapy as compared to monotherapy with the components of the combination.

Assessment of Suppression of Gastric Acid Following Histamine Stimulation. The ability of the combination therapy to suppress gastric acid can be assessed using the fundic pouch dog model. More specifically, following starvation overnight a dog is subjected to sterile ventrotomy under anesthesia using sodium pentobarbital (about 30 mg/kg, i.v.) and a fistula is attached to a part of the corpus ventriculi. After a two week recovery period, the dog is fixed to the Pavlov's stand, and gastric juice is collected every 15 minutes for about 4 hours under histamine stimulation (about 0.2 mg/kg/hr). A volume of each collected juice is recorded and the juice is titrated with 0.01 N NaOH using pH automatic measuring apparatus. The amount of gastric juice secreted in calculated as mEq/4hr. The combination therapy is then orally administered about one hour before histamine administration and gastric juice is collected and analyzed as described for the control group.

Comparison of the amount of gastric acid secreted for the Control and Treated Groups is conducted to assess the ability of the combination therapy to suppress gastric acid secretion.

Assessment of Suppression of Gastric Acid Following Tetragastrin Stimulation. The method described above using histamine as the stimulating agent is conducted to assess the ability of the combination therapy to suppress gastric acid secretion but using tetragastrin as the stimulating agent (2 μg/kg/hr).

Acid Clearance and pH Monitoring. pH monitoring is also conducted in animals. Suitable examples of experimental studies can be found in: Gawad, K. A., et al, Ambulatory long-term pH monitoring in pigs, Surg. Endosc, (2003); Johnson, S. E. et al.. Esophageal Acid Clearance Test in Healthy Dogs, Can. J. Vet. Res. 53(2): 244-7 (1989); and Cicente, Y. et al., Esophageal Acid Clearance: More Volume-dependent Than Motility Dependent in Healthy Piglets, J. Pediatr. Gastroenterol. Nutr. 35(2): 173-9 (2002). In vivo Test System. Esophageal smooth muscle peristalsis and lower esophageal spincter (LES) pressure is recorded in vivo in a feline model, similar to the one used by Liu J, Pehlivanov N, and Mittal RK in a study, wherein baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats. ( Am J Physiol Gastrointest Liver Physiol. 283:1276-81, 2002). Healthy adult cats of either sex are housed in separate cages and examined by veterinarian. The cats are allowed 2 weeks of acclimation before initiating the experiments. Only animals that are healthy and show normal behavior are used. All animals have free access to food and water throughout the course of the study. Upon completion of the study, the animals are euthanized by i.v. infusion of Euthasol.

Experimental Series. Twelve cats are used for the experiments. Multiple experiments are performed in a single cat. A rest period of 7 days is required between doses. The cats are randomly divided into groups of a-g below: a. Baclofen (0.1 μmol/kg i.v.) on LES pressure in response to 3 gastric distensions (n = 6 cats/group) b. Baclofen (1 μmol/kg i.v.) on LES pressure in response to 3 gastric distensions (n = 6 cats/group) c. Baclofen (10 μmol/kg i.v.) on LES pressure in response to 3 gastric distensions (n = 6 cats/group) d. MKC-733 (0.1 mg/kg intragastric infusion) on LES pressure in response to 3 gastric distensions (n = 6 cats/group) e. MKC-733 (1 mg/kg intragastric infusion) on LES pressure in response to

3 gastric distensions (n = 6 cats/group) f. MKC-733 (10 mg/kg intragastric infusion) on LES pressure in response to 3 gastric distensions (n = 6 cats/group) g. Combination of MKC-733 and baclofen on LES pressure in response to 3 gastric distension. The doses for MKC-733 and baclofen are threshold doses determined above (n = 6 cats/group)

Fresh solutions of the drugs are prepared for each experiment. MKC-733 is dissolved in 1.5% methylcellulose in distilled water and administered via intragastric infusion through a silicone line placed into the stomach parallel to the manometric catheter. Baclofen is purchased from Sigma (St. Louis, MO) and fresh solution is made in saline prior to the experiments. Baclofen is administered intravenously. Drugs are administered prior to the recording session. Each session starts with a 10- min recording of basal activity followed by 3 consecutive gastric distensions. MKC- 733 is administered 15-minutes prior to initiating the recording. The drug combination is administered as follows: MKC-733 via intragastric infusion and baclofen i.v. at 15-min of MKC-733 treatment. The cats are allowed a minimum of 5 days for washout and recovery between the recording sessions.

Recording of LES pressure and induction of TLESRs by gastric distension. The cats are fasted overnight and anesthetized with ketamine (75 mg per animal i.m.) Additional doses of ketamine are administered as needed throughout the experiment to maintain sedation but not alter the ability of the cat to swallow or the tone of the LES. The animals are placed on a heating blanket (37 ⁰C) to maintain body temperature. Distal esophageal motility and LES pressure is recorded manometrically by means of a water-perfused catheter assembly system (Arndorfer Inc. Greendale, WI) attached via pressure transducers to a minimally compliant hydraulic pump. LES pressure is monitored using a Dent sleeve positioned within the LES, with the tip placed into the stomach. The probe is constructed for cat esophageal manometry with a total distance of 4 cm between recording sites 0 (tip in the stomach) and 2, while the remaining sites (3, 4 and 5) are placed 2 cm apart with site 5 placed at 6 cm from the top of the sleeve. The outputs from the pressure transducers are connected to bridge amplifiers and the signal from each manometric site is recorded using an 8 channel Power Lab (AD Instruments). Under these experimental conditions, the effect of gastric distension on LES pressure is studied by injecting 60 ml of air into the stomach. Gastric distension is induced by air injected into the stomach using a hand-held syringe. The recording session ensures the reproduction of the TLSRs reported by Liu et al Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 283(6): G 1276-81, where a gastric distension with 60 ml of air consistently induces a LES relaxation. The air is injected within 5-10 s, kept in the stomach for a period of 60 s and then withdrawn using the syringe. The volume of withdrawn air is measured and about 80-90 % of the injected air is recovered from the stomach after each gastric distension. Gastric distensions is repeated 3 times in each animal. At least 2-min interval is allowed between distensions. According to the protocol, if an esophageal contraction occurs immediately after air injection, the distension is terminated by withdrawing air from the stomach and the data for LES pressure is disregarded.

Data Analysis and statistics. The effects of baclofen, MKC-733 or a combination of both on the LES relaxation induced by stomach distension are investigated in each animal. The treatments are randomized and the final results are expressed as mean ± SEM from 6 experiments in different animals for each treatment. Basal LES pressure is measured for a 10 s period immediately before the gastric distension. The relaxation of LES is measured by the decrease (<50%) in basal LES pressure in response to gastric distention. The durations of TLESRs are calculated for each treatment. One way ANOVA and Bonferroni's MCT or Student's t-test is used to compare the effects of baclofen, MKC-733 or their combination. Differences is considered significant at p<0.05.

While this invention has been particularly shown and described with references to embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a gastrointestinal motility disorder in a subject in need of such treatment comprising coadministering to said subject: a) an effective amount of a 5-HT₃ receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof; and b) an effective amount of a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

2. The method of Claim 1 , wherein the subject is a human.

3. The method of Claim 1, wherein the gastrointestinal motility disorder is gastroesophageal reflux disease (GERD).

4. The method of Claim 3, wherein the GERD is nocturnal GERD.

5. The method of Claim 1, wherein the gastrointestinal motility disorder is gastroparesis.

6. The method of Claim 1 , wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof

7. The method of Claim 1, wherein the GABA receptor agonist is baclofen or a pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The method of Claim 1 , wherein the 5-HT₃ receptor agonist is a thieno[3,2-b]pyridine derivative.

9. The method of Claim 8, wherein the 5-HT₃ receptor agonist is represented by Structural Formula I:

wherein:

Ri represents hydrogen, a C]-C₆ alkyl group, a C₂-Ce alkenyl group, a C₂-C₆ alkynyl group, a C₃-Cs cycloalkyl group, a C₆-Ci₂ aryl group or a C₇-Ci_S aralkyl group;

R2 represents hydrogen, a Ci-Cβ alkyl group, halogen, hydroxyl, a Ci-C₆ alkoxy group, amino, a Ci-C₆ alkylamino group, nitro, mercapto or a C]-C₆ alkylthio group;

Y represents -O- or

wherein R₃ represents hydrogen or a Ci-Ce alkyl group; and

A is represented by

or

IV

wherein: n is an integer from 1 to about 4; R₄ represents hydrogen, a Ci-C₆ alkyl group, a C₃-C8 cycloalkyl group or a C₇-C ₁₈ aralkyl group; or a tautomer, pharmaceutically acceptable salt, solvate, hydrate or N- oxide derivative thereof.

10. The method of Claim 9, wherein the 5-HT₃ receptor agonist of Structural Formula I is an N-oxide derivative.

1 1. The method of Claim 9, wherein:

H

Y represents -O- or ^N ;

Rj represents hydrogen, a Cj-C₆ alkyl group, a C₆-Ci₂ aryl group, or a C₇-C is aralkyl group; R₂ represents hydrogen, a Cj-C₆ alkyl group or halogen; and

A is represented by

wherein: n is 2 or 3; and R₄ represents a C 1 -Ce alkyl group.

12. The method of Claim 9, wherein R| represents hydrogen or a C₁-C₃ alkyl group; R₂ represents hydrogen, a C1-C₃ alkyl group or halogen; R₃ represents hydrogen; R₄ represents a C₁-C₃ alkyl group and n is an integer of 2 or 3.

13. The method of Claim 9, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l -aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1 ]hept-7-yl)acetic acid and a combination thereof.

14. The method of Claim 9, wherein the GABA receptor agonist is baclofen.

15. The method of Claim 9, wherein the 5-HT₃ receptor agonist is represented by Structural Formula V:

or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

16. The method of Claim 15, wherein the asterisked carbon atom is in the (R) configuration.

17. The method of Claim 16, wherein the 5-HT₃ agonist is in the form of the monohydrochloride salt.

18. The method of Claim 16, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP-19986, gabapentin, pregabalin, PD217.014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

19. The method of Claim 16, wherein the GABA receptor agonist is baclofen.

20. The method of Claim 1, wherein the 5-HT₃ receptor agonist is represented by Structural Formula VI or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof:

wherein:

R represents hydrogen, halogen, hydroxyl, a Cj-Ce alkoxy group, carboxy, a Ci-Ce alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;

C A ) — is a phenyl ring or a naphthalene ring;

Li and L₂ are defined so that one is a direct bond and the other is: a) a C_J-C₆ alkylene group optionally containing an interrupting oxygen or sulfur atom therein; b) an oxygen atom or sulfur atom; or c) a C]-C₆ alkenylene group;

L is a direct bond or a Ci-C₆ alkylene group; and

Im represents a group having the formula:

wherein:

Ri-R^ are the same or different each representing hydrogen or a Ci-Cή alkyl group.

21. The method of Claim 20, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP-19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l -aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyI)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

22. The method of Claim 20, wherein the GABA receptor agonist is baclofen.

23. The method of Claim 20, wherein ^-^ is a phenyl ring; Li is a direct bond; and L₂ is an alkylene group or alkenylene group.

24. The method of Claim 20, wherein the compound is represented by Formula VII:

or a tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

25. The method of Claim 24, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3. l]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

26. The method of Claim 24, wherein the GABA receptor agonist is baclofen.

27. A method of increasing esophageal motility in a subject in need thereof comprising coadministering an effective amount of a 5-HT₃ receptor agonist and an effective amount of a GABA receptor agonist.

28. The method of Claim 27, wherein the subject is a human.

29. The method of Claim 27, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP-19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-( 1 R,3 S)-( 1 -(aminomethyl)-3 - methylcyclohexane)acetic acid, lα,3α,5α-(l -aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof

30. The method of Claim 27, wherein the GABA receptor agonist is baclofen or a pharmaceutically acceptable salt, hydrate or solvate thereof.

31. The method of Claim 27, wherein the 5-HT3 receptor agonist is a thieno[3,2-b]pyridine derivative.

32. The method of Claim 31 , wherein the 5-HT₃ receptor agonist is represented by Structural Formula I:

wherein:

Ri represents hydrogen, a Ci-C₆ alkyl group, a C₂-Cg alkenyl group, a C₂-Ce alkynyl group, a C₃-C₈ cycloalkyl group, a C₆-Cj₂ aryl group or a C₇-C is aralkyl group;

R₂ represents hydrogen, a Cj-C₆ alkyl group, halogen, hydroxy!, a Cj-C₆ alkoxy group, amino, a Ci-C₆ alkylamino group, nitro, mercapto or a Ci-C₆ alkylthio group;

Y represents -O- or — wherein R₃ represents hydrogen or a Ci-C₆ alkyl group; and A is represented by

wherein: n is an integer from 1 to about 4;

R₄ represents hydrogen, a C_I-C_O alkyl group, a C₃-Ce cycloalkyl group or a C₇-C is aralkyl group; or a tautomer, pharmaceutically acceptable salt, solvate, hydrate or N- oxide derivative thereof.

33. The method of Claim 32, wherein the 5-HT₃ receptor agonist of Structural Formula I is an N-oxide derivative.

34. The method of Claim 32, wherein:

H

Y represents -O- or N ;

Ri represents hydrogen, a Ci-Cβ alkyl group, a C₆-C12 aryl group, or a C₇-Ci₈ aralkyl group;

R₂ represents hydrogen, a Ci-C₆ alkyl group or halogen; and A is represented by

wherein: n is 2 or 3; and

R₄ represents a Ci-Cβ alkyl group.

35. The method of Claim 32, wherein Ri represents hydrogen or a C1-C3 alkyl group; R₂ represents hydrogen, a C1-C3 alkyl group or halogen; R3 represents hydrogen; R₄ represents a C₁-C₃ alkyl group and n is an integer of 2 or 3.

36. The method of Claim 32, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

37. The method of Claim 32, wherein the GABA receptor agonist is baclofen.

38. The method of Claim 32, wherein the 5-HT₃ receptor agonist is represented by Structural Formula V:

or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

39. The method of Claim 38, wherein the asterisked carbon atom is in the (R) configuration.

40. The method of Claim 39, wherein the 5-HT₃ agonist is in the form of the monohydrochloride salt.

41. The method of Claim 39, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217.014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(l R,3S)-(1 -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

42. The method of Claim 39, wherein the GABA receptor agonist is baclofen.

43. The method of Claim 27, wherein the 5-HT₃ receptor agonist is represented by Structural Formula VI or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof:

wherein:

R represents hydrogen, halogen, hydroxyl, a Ci-Cβ alkoxy group, carboxy, a Cj-Cβ alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;

C A )

^-^ is a phenyl ring or a naphthalene ring;

Li and L₂ are defined so that one is a direct bond and the other is: a) a Ci-Ce alkylene group optionally containing an interrupting oxygen or sulfur atom therein; b) an oxygen atom or sulfur atom; or c) a C)-C_O alkenylene group;

L is a direct bond or a Cj-Cβ alkylene group; and Im represents a group having the formula:

wherein:

Ri-R^ are the same or different each representing hydrogen or a Ci-Ce alkyl group.

44. The method of Claim 43, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(l R,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

45. The method of Claim 43, wherein the GABA receptor agonist is baclofen.

( A )

46. The method of Claim 43, wherein — is a phenyl ring; Li is a direct bond; and L₂ is an alkylene group or alkenylene group.

47. The method of Claim 43, wherein the compound is represented by

Formula VII:

or a tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

48. The method of Claim 47, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(l S,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

49. The method of Claim 47, wherein the GABA receptor agonist is baclofen.

50. A pharmaceutical composition comprising an effective amount of a 5- HT₃ receptor agonist and an effective amount of a GABA receptor agonist.

51. The method of Claim 50, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof

52. The method of Claim 50, wherein the GABA receptor agonist is baclofen or a pharmaceutically acceptable salt, hydrate or solvate thereof.

53. The method of Claim 50, wherein the 5-HT₃ receptor agonist is a thieno[3,2-b]pyridine derivative.

54. The method of Claim 53, wherein the 5-HTj receptor agonist is represented by Structural Formula I:

wherein:

Ri represents hydrogen, a Ci-C₆ alkyl group, a C₂-C₆ alkenyl group, a C2-C6 alkynyl group, a C₃-C8 cycloalkyl group, a C₆-Ci₂ aryl group or a C7-C18 aralkyl group; R₂ represents hydrogen, a Ci-C₆ alkyl group, halogen, hydroxyl, a C i -C_O alkoxy group, amino, a Ci-C₆ alkylamino group, nitro, mercapto or a Ci-C₆ alkylthio group; f

Y represents -O- or ^N wherein R₃ represents hydrogen or a Ci-C₆ alkyl group; and A is represented by

wherein: n is an integer from 1 to about 4;

R₄ represents hydrogen, a Ci-Ce alkyl group, a C₃-Cs cycloalkyl group or a C₇-CiS aralkyl group; or a tautomer, pharmaceutically acceptable salt, solvate, hydrate or N- oxide derivative thereof.

55. The method of Claim 54, wherein the 5-HT₃ receptor agonist of Structural Formula I is an N-oxide derivative.

56. The method of Claim 54, wherein:

H Y represents -O- or — N — ;

Ri represents hydrogen, a Cj-C₆ alkyl group, a C₆-Ci₂ aryl group, or a C₇-C₁₈ aralkyl group; R₂ represents hydrogen, a Ci -CO alkyl group or halogen; and A is represented by

wherein: n is 2 or 3; and

R₄ represents a Ci-C₆ alkyl group.

57. The method of Claim 54, wherein Rj represents hydrogen or a C1-C₃ alkyl group; R₂ represents hydrogen, a C₁-C₃ alkyl group or halogen; R₃ represents hydrogen; R₄ represents a C₁-C₃ alkyl group and n is an integer of 2 or 3.

58. The method of Claim 54, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(l S,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3. l]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1 ]hept-7-yl)acetic acid and a combination thereof.

59. The method of Claim 54, wherein the GABA receptor agonist is baclofen.

60. The method of Claim 54, wherein the 5-HTs receptor agonist is represented by Structural Formula V:

or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

61. The method of Claim 60, wherein the asterisked carbon atom is in the (R) configuration.

62. The method of Claim 61, wherein the 5-HT₃ agonist is in the form of the monohydrochloride salt.

63. The method of Claim 61, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217.014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l -aminomethyl)- (3,5- dimethy lcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ] non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

64. The method of Claim 60, wherein the GABA receptor agonist is baclofen.

65. The method of Claim 50, wherein the 5-HT₃ receptor agonist is represented by Structural Formula VI or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof:

wherein:

R represents hydrogen, halogen, hydroxyl, a Ci-C₆ alkoxy group, carboxy, a Ci-Ce alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;

is a phenyl ring or a naphthalene ring;

Li and L₂ are defined so that one is a direct bond and the other is: a) a Ci-C₆ alkylene group optionally containing an interrupting oxygen or sulfur atom therein; b) an oxygen atom or sulfur atom; or c) a Ci-C₆ alkenylene group;

L is a direct bond or a Ci-C₆ alkylene group; and Im represents a group having the formula:

wherein:

Ri -R_s are the same or different each representing hydrogen or a C_J-C₆ alkyl group.

66. The method of Claim 65, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

67. The method of Claim 65, wherein the GABA receptor agonist is baclofen.

( A )

68. The method of Claim 65, wherein ^-^ is a phenyl ring; Li is a direct bond; and L₂ is an alkylene group or alkenylene group.

69. The method of Claim 65, wherein the compound is represented by

Formula VII:

or a tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

70. The method of Claim 69, wherein the GABA receptor agonist is selected from the group consisting of baclofen, XP-19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, lα,3α,5α-(l -aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9- yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

71. The method of Claim 69, wherein the GABA receptor agonist is baclofen.