Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds.
Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.
Department of Medical Affairs, Novartis Pharmaceuticals Inc., 59 Route 10, East Hanover, NJ 07936, USA.
Michael J
MJ
Callahan
D001341:Autonomic Nervous System / Q000187:drug effects*; D018680:Cholinergic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D003109:Colonic Diseases, Functional / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D010277:Parasympathomimetics / Q000494:pharmacology / Q000627:therapeutic use*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D011957:Receptors, Opioid / Q000819:agonists; D011985:Receptors, Serotonin / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D035703:Therapies, Investigational; D016896:Treatment Outcome
D018680:Cholinergic Antagonists; D010277:Parasympathomimetics; D011949:Receptors, Cholecystokinin; D011957:Receptors, Opioid; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D018039:Receptors, Tachykinin