title: New 5-HT3 (serotonin-3) receptor antagonists, II. Synthesis and structure-activity relationships of pyrimido[1,6-a]indoles.
abstract: A series of pyrimido[1,6-alpha]indol-1(2H)-ones was prepared and evaluated for 5-HT3 receptor antagonist activity. The compounds in this series were regarded as bioisosters of the pyrido[1,2-alpha]indol-6(7H)-ones previously reported. High potency was found for compounds having 5-methyl substituents on both the pyrimido[1,6-alpha]indole ring and the imidazole ring. Optimized members of this series, 8b and (+)-26a, were potent 5-HT3 receptor antagonists as determined by measuring inhibition of the Bezold-Jarisch reflex in anesthetized rats (ED50 0.6 and 0.8 microgram/kg i.v., respectively), being equipotent to or more potent than FK 1052 (1) in the previous paper and 20- to 30-fold more potent than ondansetron (2).
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Nishino
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Yamakuni
authors.forename: H
authors.initials: H
authors.lastname: Takasugi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D012702:Serotonin Antagonists; D017294:Ondansetron