Kawakita T, Kuroita T, Yasumoto M, Sano M, Inaba K, Fukuda T, Tahara T
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
Chem Pharm Bull (Tokyo). 1992 Mar;40(3):624-30. doi: 10.1248/cpb.40.624.
A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.
合成了一系列3,4-二氢-3-氧代-1,4-苯并恶嗪-8-甲酰胺衍生物，并通过它们拮抗大鼠贝佐尔德-贾里什（BJ）效应的能力来评估其对5-羟色胺3（5-HT3）受体的拮抗活性。带有1-氮杂双环[2.2.2]辛-3-基部分作为连接在8位甲酰胺上的碱性官能团的衍生物，比带有其他三种碱性基团的衍生物表现出更强的拮抗活性。该系列的构效关系表明，甲基和氯原子分别作为4位和6位的取代基更有效。该系列中的代表性化合物15（Y-25130）对BJ效应表现出强效拮抗活性（静脉注射半数有效量ED50 = 1.3微克/千克），对5-HT3受体具有高亲和力（抑制常数Ki = 2.9纳摩尔），并且在静脉注射剂量为0.1毫克/千克时能完全预防犬顺铂诱导的呕吐。
