Kato M, Nishino S, Ito K, Yamakuni H, Takasugi H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1994 Dec;42(12):2556-64. doi: 10.1248/cpb.42.2556.
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).
合成了一系列嘧啶并[1,6-α]吲哚-1(2H)-酮，并对其5-羟色胺3（5-HT3）受体拮抗剂活性进行了评估。该系列化合物被视为先前报道的吡啶并[1,2-α]吲哚-6(7H)-酮的生物电子等排体。发现嘧啶并[1,6-α]吲哚环和咪唑环上均具有5-甲基取代基的化合物具有高效力。通过测量麻醉大鼠的贝佐尔德-雅里什反射抑制作用确定，该系列的优化成员8b和(+)-26a是强效5-HT3受体拮抗剂（ED50分别为0.6和0.8微克/千克静脉注射），与前文的FK 1052（1）效力相当或更强，且比昂丹司琼（2）强20至30倍。
