Kuroita T, Sakamori M, Kawakita T
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Chem Pharm Bull (Tokyo). 1996 Apr;44(4):756-64. doi: 10.1248/cpb.44.756.
Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT3) receptor binding affinity. The 5-HT3 receptor antagonistic activity of zacopride, a representative 5-HT3 receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromatic moiety by a 3-dimethyl-amino substituent. This finding prompted a structural modification of azasetron, another 5-HT3 receptor antagonist. Consequently, a new series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamides was obtained and these compounds were found to be more potent than 3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxamides. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3,4-dihydro-4-methyl-2H-1,4 -benzoxazine-8-carboxamide showed a high affinity for 5-HT3 receptors K(i) = 0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED50 = 0.089 micrograms/kg i.v.) in rats.
合成了几种3-取代的5-氯-2-甲氧基苯甲酰胺，并对其进行了5-羟色胺-3（5-HT3）受体结合亲和力评估。扎考必利是一种代表性的5-HT3受体拮抗剂，用3-二甲基氨基取代芳香部分上的4-氨基取代基后，其5-HT3受体拮抗活性未发生变化。这一发现促使对另一种5-HT3受体拮抗剂阿扎司琼进行结构修饰。结果，得到了一系列新的3,4-二氢-2H-1,4-苯并恶嗪-8-甲酰胺，发现这些化合物比3,4-二氢-3-氧代-2H-1,4-苯并恶嗪-8-甲酰胺更有效。特别是，（S）-N-（1-氮杂双环[2.2.2]辛-3-基）-6-氯-3,4-二氢-4-甲基-2H-1,4-苯并恶嗪-8-甲酰胺对5-HT3受体表现出高亲和力（K(i)=0.051 nM），并且对大鼠的贝佐尔德-雅里什反射具有特别强的拮抗活性（ED50 = 0.089微克/千克静脉注射）。
