New 5-HT3 (serotonin-3) receptor antagonists. I. Synthesis and structure-activity relationships of pyrido[1,2-a]indoles.
A series of pyrido[1,2-alpha]indol-6(7-H)-ones was prepared and evaluated for 5-HT3 receptor antagonist activity. The structural requirements for the 5-HT3 receptor antagonist have been defined as an aromatic moiety, a basic nitrogen, and a linking acyl group. The (5-methylimidazol-4-yl)methyl group as a basic nitrogen moiety was an important element for high potency. The highest potency was observed for compounds which have 7- and 10-methyl substituents on the pyrido[1,2-alpha]indol-6(7H)-one ring. From this series, (+)-11b (FK 1052) was selected for further evaluation. FK 1052 was a potent 5-HT3 receptor antagonist in the Bezold-Jarisch reflex test in rats (ED50 0.9 microgram/kg, i.v.) and a very effective antiemetic agent against cisplatin-induced emesis in dogs (ED50 1.2 x 2 micrograms/kg, i.v. and 2.7 x 2 micrograms/kg, p.o.).
Kato
M
M
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd. Osaka, Japan.
Ito
K
K
Nishino
S
S
Yamakuni
H
H
Takasugi
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D007211:Indoles; D012702:Serotonin Antagonists; D002945:Cisplatin