Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. Synthesis and structure-activity relationships of 9-methyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-4-one derivatives.
Novel 9-methyl-4,9-dihydrothiopyrano[2,3-b]indol-4-one derivatives 2b-e, 3-methylene-9-methyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-4-on e derivatives 3b-e and 9-methyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-4-one derivatives 4a-e were prepared. The 5-hydroxytryptamine (5-HT3) receptor-antagonistic activities of these compounds were evaluated by using the von Bezold-Jarisch reflex test (B. J. reflex, rats) and the contractile response to 5-HT in the isolated distal colon (guinea pig). The 5-ethyl-4-imidazolyl derivative 4d was found to be 79 times more potent than ondansetron 1 in the B. J. reflex test (ID50 = 0.048 microgram/kg, i.v.), and the 5-methyl-4-imidazolyl derivative 4c was found to be 126 times more potent than 1 in the colonic contraction (IC50 = 0.0062 microM) assay.
Suzuki
T
T
Neuroscience/Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Matsuhisa
A
A
Miyata
K
K
Yanagisawa
I
I
Ohta
M
M
D000818:Animals; D003106:Colon / Q000187:drug effects; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C104688:9-methyl-3-((5-ethylimidazol-4-yl)methyl)-2,3,4,9-tetrahydrothiopyrano(2,3-b)indol-4-one; C104687:9-methyl-3-((5-methylimidazol-4-yl)methyl)-2,3,4,9-tetrahydrothiopyrano(2,3-b)indol-4-one fumarate; D007093:Imidazoles; D007211:Indoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D012701:Serotonin; D017294:Ondansetron