MUSCARINIC ANALGESICS WITH POTENT AND SELECTIVE EFFECTS ON THE GASTROINTESTINAL-TRACT - POTENTIAL APPLICATION FOR THE TREATMENT OF IRRITABLE-BOWEL-SYNDROME

Irritable bowel syndrome (IBS) is a pathopysiolocal condition characte rized by abnormal bowel habits that are frequently accompanied by abdo minal pain. Current therapy based on reducing high-amplitude GI contra ctions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. W e have previously found potent antinociceptive agents acting through m uscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activ ity as analgesics in the mouse withing assay and for activity in norma lizing spontaneous cluster contractions in ferret jejunum as a model o f IBS in humans. ]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane (3 5, LY316108/NNC11-2192) was found to offer an exceptional profile comb ining analgesic potency in mouse writhing (ED(50) = 0.1 mg/kg) along w ith potency for normalization of GI motility (ED(50) = 0.17 mg/kg). Th is combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.