Watanabe T, Kakefuda A, Kinoyama I, Takizawa K, Hirano S, Shibata H, Yanagisawa I
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1997 Sep;45(9):1458-69. doi: 10.1248/cpb.45.1458.
A series of succinamide derivatives containing the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton (6a-z) was prepared and evaluated for binding affinity to muscarinic receptors in vitro and for antagonism of bradycardia and salivation in vivo in comparison with AF-DX 116 (1a). Structure-activity relationships (SAR) studies in vitro indicated that the 4-(4-alkyl-1-piperazinyl)benzylamino moiety plays a crucial role in enhancing the affinity for M2 muscarinic receptors. Compound 6y, containing a 4-(4-isopropyl-1-piperazinyl)benzylmethylamino moiety, exhibited the highest affinity for M2 muscarinic receptors (pKi = 9.2), being 200 times as potent as 1a, and compound 6u, containing a 4-(4-ethyl-1-piperazinyl)benzylethylamino moiety, showed the highest selectivity for M2 over M3 muscarinic receptors (M3/M2 ratio = 320). Both 6y and 6u antagonized the oxotremorine-induced bradycardia in rats after intravenous or oral administration. Oral evaluation in conscious dogs showed that the efficacy for increasing the heart rate was at least 3-fold greater than that of 1a.
制备了一系列含有5,11-二氢-6H-吡啶并[2,3-b][1,4]苯并二氮杂卓-6-酮骨架的琥珀酰胺衍生物（6a-z），并与AF-DX 116（1a）比较，评估了它们在体外对毒蕈碱受体的结合亲和力以及在体内对心动过缓和唾液分泌的拮抗作用。体外构效关系（SAR）研究表明，4-（4-烷基-1-哌嗪基）苄基氨基部分在增强对M2毒蕈碱受体的亲和力方面起着关键作用。含有4-（4-异丙基-1-哌嗪基）苄基甲基氨基部分的化合物6y对M2毒蕈碱受体表现出最高的亲和力（pKi = 9.2），效力是1a的200倍，而含有4-（4-乙基-1-哌嗪基）苄基乙基氨基部分的化合物6u对M2毒蕈碱受体的选择性高于M3毒蕈碱受体（M3/M2比值 = 320）。静脉注射或口服后，6y和6u均可拮抗大鼠中氧化震颤素诱导的心动过缓。清醒犬的口服评估表明，增加心率的效力至少是1a的3倍。
