Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro.
We investigated the in vitro pharmacological profile of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate). In cloned human 5-HT3A receptors, YM-31636 had a pKi value of 9.67 vs. ramosetron and pKi values for other 5-HT3 receptor agonists were less than 7. YM-31636 showed very low affinities for other receptors. YM-31636 induced contraction of isolated guinea pig distal colon. The intrinsic activity was approximately 0.90 compared with 5-hydroxytryptamine's (5-HT) 1.0, and the potency was 26 times greater than that of 5-HT. YM-31636 increased short-circuit current (Isc) in the isolated guinea pig distal colon. In this case, the relative intrinsic activity was approximately 0.19. In isolated guinea pig right atrium, YM-31636 induced tachycardia with the relative intrinsic activity of approximately 0.23. All these effects of YM-31636 were antagonized by ramosetron, a selective 5-HT3 receptor antagonist. These results suggest that YM-31636 is a potent and selective 5-HT3 receptor agonist, preferentially acting on the contraction of the colon.
Ito
H
H
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. ito@yamanouchi.co.jp
Kiso
T
T
Miyata
K
K
Kamato
T
T
Yuki
H
H
Akuzawa
S
S
Nagakura
Y
Y
Yamano
M
M
Suzuki
M
M
Naitoh
Y
Y
Sakai
H
H
Iwaoka
K
K
Yamaguchi
T
T
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D016275:Atrial Function; D001645:Biguanides / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
C419869:2-(1H-imidazol-4-ylmethyl)-8H-indeno(1,2-d)thiazole; D000880:Anthraquinones; D001645:Biguanides; D011758:Pyrroles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D012701:Serotonin; C045918:2-methyl-5-HT; C065734:1-(3-chlorophenyl)biguanide; D015232:Dinoprostone; D000109:Acetylcholine; C020491:rhein