New 5-HT_3 (Serotonin-3) Receptor Antagonists. I. Synthesis and Structure-Activity Relationships of Pyrido[1,2-α]indoles

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A series of pyrido[1,2-α]indol-6(7H)-ones was prepared and evaluated for 5-HT_3 receptor antagonist activity. The structural requirements for the 5-HT_3 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-α]indol-6(7H)-one ring. From this series, (+)-11b (FK 1052) was selected for further evaluation. FK 1052 was a potent 5-HT_3 receptor antagonist in the Bezold-Jarisch reflex test in rats (ED_<50> 0.9 μg/kg, i.v.) and a very effective antiemetic agent against cisplatin-induced emesis in dogs (ED_<50> 1.1×2 μg/kg, i.v. and 2.7×2 μg/kg, p.o.).
社団法人日本薬学会の論文
1994-12-15