title: Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome.
abstract: We examined the pharmacological profile of ramosetron, a 5-HT(3)-receptor antagonist for irritable bowel syndrome with diarrhea, comparing it with those of other 5-HT(3)-receptor antagonists, alosetron and cilansetron, and the anti-diarrheal agent loperamide. Ramosetron showed high affinity for cloned human and rat 5-HT(3) receptors, with K(i) values of 0.091 +/- 0.014 and 0.22 +/- 0.051 nmol/L, respectively, while its affinities for other receptors, transporters, ion channels, and enzymes were negligible. Dissociation of ramosetron from the human 5-HT(3) receptor was extremely slow (t(1/2) = 560 min), while alosetron (t(1/2) = 180 min) and cilansetron (t(1/2) = 88 min) dissociated relatively rapidly. Ramosetron competitively inhibited 5-HT-induced contraction of isolated guinea-pig colon, with pA(2) values of 8.6 (8.5 - 9.0). Ramosetron given orally also dose-dependently inhibited the von Bezold-Jarisch reflex in rats, with an ED(50) value of 1.2 (0.93 - 1.6) microg/kg. In addition, oral ramosetron dose-dependently inhibited restraint stress-induced defecation in rats, with an ED(50) value of 0.62 (0.17 - 1.2) microg/kg. In all of these experiments, the potencies of ramosetron were greater than those of alosetron, cilansetron, or loperamide. These results indicate that ramosetron is a highly potent and selective 5-HT(3)-receptor antagonist, with beneficial effects against stress-induced abnormal defecation in rats.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma, Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. takuya.hirata@jp.astellas.com
authors.forename: Takuya
authors.initials: T
authors.lastname: Hirata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Keto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Funatsu
authors.forename: Shinobu
authors.initials: S
authors.lastname: Akuzawa
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D003106:Colon / Q000187:drug effects; D003672:Defecation / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects; D012149:Restraint, Physical; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013315:Stress, Psychological / Q000503:physiopathology / Q000523:psychology
chemical_list: D001562:Benzimidazoles; D002227:Carbazoles; D002243:Carbolines; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; D007473:Ion Channels; D011725:Pyridines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C090840:alosetron; C084473:cilansetron; D008139:Loperamide; C071315:ramosetron