Dopamine 3 receptor agonist and antagonist treatment of gastrointestinal motility disorders

Abstract

Provided herein are methods of treating gastrointestinal motility disorders by targeting the dopamine 3 receptor (D3R). A D3R agonist is administered to a subject to decrease gastrointestinal motility to treat the disorder. A D3R antagonist is administered to a subject to decrease gastrointestinal motility to treat the disorder.

1 . A method of treating a gastrointestinal motility disorder associated with an increase in gastrointestinal motility in a subject, comprising the step of:
 administering a therapeutically effective amount of a dopamine 3 receptor agonist or a pharmaceutically acceptable salt thereof to the subject.   
     
     
         2 . The method of  claim 1 , wherein the subject is an animal or a human. 
     
     
         3 . The method of  claim 1 , wherein the gastrointestinal motility disorder is at least one of inflammatory bowel disease, ulcerative colitis, granulomatous enteritis, an infectious disease of the small or large intestine, pyloric spasm, abdominal cramps, a functional bowel disorder, mild dysenteries, diverticulitis, acute enterocolitis, neurogenic bowel disorders, splenic flexure syndrome, neurogenic colon, or spastic colitis. 
     
     
         4 . The method of  claim 1 , wherein the increase in gastrointestinal motility is caused by one or more medications. 
     
     
         5 . The method of  claim 1 , wherein the dopamine 3 receptor agonist is PD 128907 hydrochloride or 7-hydroxy-2-dipropylaminotetralin. 
     
     
         6 . The method of  claim 1 , wherein the agonist of dopamine 3 receptor is present in a pharmaceutically acceptable sustained release formulation. 
     
     
         7 . The method of  claim 1 , further comprising:
 administerting the dopamine 3 receptor agonist in combination with at least one other pharmaceutically active compound.   
     
     
         8 . The method of  claim 7 , wherein the at least one other pharmaceutically active compound is a ganglionic blocker, a nicotinic-receptor antagonist, a gastrointestinal motility altering agent, antispasmodic, an antimuscarinic agent, an opiate, a 5-HT receptor agonist, a 5-HT receptor antagonist, a calcium channel blocker, a beta adrenergic receptor blocker, an agent that alters fluid transport across the gut, an agent that alters fluid transport into or out of gastrointestinal cells, a diuretic, an anti-diarrheal, an H 2 -antihistamine, a proton pump inhibitor, an antacid, an anti-inflammatory agent, a steroid, a mineralocorticoid, a corticosteroid, an anti-infective agent, an immunomodulator, or fish oil. 
     
     
         9 . The method of  claim 8 , wherein the at least one other pharmaceutically active compound is hexamethonium, trimethaphan, chloroisondamine, erysodine, beta.-dihydroerythrodine, amantidine, perpidine, succinylcholine, decamethonium, tubocurarine, atracurium, doxacurium, mivicurium, pancuronium, rocuronium, vencuronium, glycopyrrolate, atropine, hyscomine, scopolamine, loperamide, difenoxine, codeine, morphine, oxymorphone, oxycontin, dihydrocodeine, fentanyl, alosetron hydrochloride, verapamil, amiloride, furosemide, bismuth, sandostatin, sulfasalazine, estrogens, prednisone, prednisolone, cortisol, cortisone, fluticasone, dexamethasone, betamethasone, 5-aminosalicylic acid, metronidazole, ciprofloxacin, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, fish oil, remicade, heparin, or nicotine. 
     
     
         10 . The method of  claim 1 , wherein the agonist of dopamine 3 receptor is administered via oral, nasal, intradermal, parenteral, mucosal, buccal, rectal or topical route. 
     
     
         11 . A method of treating a gastrointestinal motility disorder associated with a decrease in gastrointestinal motility in a subject, comprising the step of:
 administering a therapeutically effective amount of a dopamine 3 receptor antagonist or a pharmaceutically acceptable salt thereof to the subject.   
     
     
         12 . The method of  claim 11 , wherein the subject is an animal or a human. 
     
     
         13 . The method of  claim 11 , wherein the gastrointestinal motility disorder is or caused by at least one of gastroparesis, gastroesophageal reflux disease, diabetes, infections, endocrine disorders, scleroderma, neuromuscular diseases, cancer, radiation treatment, surgery of the upper intestinal tract, surgery of the stomach, surgery of the esophagus, surgery of the duodenum, anorexia nervosa, or bulimia. 
     
     
         14 . The method of  claim 11 , wherein the decrease in gastrointestinal motility is caused by a narcotic pain medication, a calcium channel blocker or an antidepressant. 
     
     
         15 . The method of  claim 11 , wherein the antagonist of dopamine 3 receptor is UH232, GR 103691, U-99194A or nafadotride. 
     
     
         16 . The method of  claim 11 , wherein the antagonist of dopamine 3 receptor comprises a pharmaceutically acceptable sustained release formulation. 
     
     
         17 . The method of  claim 11 , further comprising:
 administerting the dopamine 3 receptor antagonist in combination with at least one other pharmaceutically active compound.   
     
     
         18 . The method of  claim 17 , wherein the at least one other pharmaceutically active compound is a proton pump inhibitor, a histamine H2 receptor blocker, an anti acid agent, a gastrointestinal stimulant, a dopamine receptor 2 blocker, a 5-HT4 agonist, a 5-Ht3 antagonist, an agent for treating anorexia, an agent for treating gall bladder stasis, an agent for treating postoperative paralytic ileus, an agent for treating scleroderma, an agent for treating intestinal pseudo-obstruction, an anti-gastritis agent, an anti-emesis agent, an anti-constipation agent, an agent for treating irritable bowel syndrome, an agent for treating functional dyspepsia, and an agent for treating colonic hypomotility. 
     
     
         19 . The method of  claim 18 , wherein the at least one other pharmaceutically active compound is esomeprazole, lansoprazole or omeprazole, nizatidine, famotidine, cimetidine, ranitidine, aluminum antacids, calcium antacids, magnesium antacids, metoclopramide, domperidone, fenoldapam mesylate, cabergoline, pramipexole, pergolide mesylate, ropinirole, amanitidine HCL, tegaserod, alosetron, pilocarpine, fluoxetine, paroxetine, erythromycin, and dexloxiglumide. 
     
     
         20 . The method of  claim 12 , wherein the antagonist of dopamine 3 receptor is administered via oral, nasal, intradermal, parenteral, mucosal, buccal, rectal or topical route.