Mannhold R, Steiner R, Haas W, Kaufmann R
Naunyn Schmiedebergs Arch Pharmacol. 1978 Apr;302(2):217-26. doi: 10.1007/BF00517988.
An investigation was carried out towards a qualitative and quantitative structure-activity relationship of verapamil based on an analysis of the frequency-dependent negative inotropic action exerted in cat papillary muscles by various groups of verapamil derivatives. (1) Substituents of the benzene ring near the asymmetric carbon atom and the isopropyl group were found to be no essential substituents for the frequency-dependent negative inotropic action of verapamil but to have a strong influence on the potency of the drug. (2) Both the tertiary amino nitrogen and the two benzene rings are essential for the frequency-dependent negative inotropic action of verapamil (3) The molecular importance of the N-methyl group is probably based on steric effects. (4) Investigations of the verapamil derivative H 1 revealed that a quaternization of the drug is followed by a total loss of effectiveness. (5) No significant correlation of the biological activity of verapamil derivatives with the partition coefficient P has been obtained. (6) Hansch analysis with verapamil derivatives of group A (= different substitution of the benzene ring near C) shows that the variance of biological activity can be optimally correlated to a combination of the Hammett constant and the molar volume. Hansch analysis of group B (= exchange of isopropyl group) led to the conclusion that hydrophobic effects are responsible for the influence of the isopropyl substituent.
基于对不同组维拉帕米衍生物在猫乳头肌中产生的频率依赖性负性肌力作用的分析，对维拉帕米的定性和定量构效关系进行了研究。（1）发现不对称碳原子附近苯环的取代基和异丙基对于维拉帕米的频率依赖性负性肌力作用不是必需的取代基，但对药物的效力有很大影响。（2）叔氨基氮和两个苯环对于维拉帕米的频率依赖性负性肌力作用都是必需的。（3）N-甲基的分子重要性可能基于空间效应。（4）对维拉帕米衍生物H 1的研究表明，药物季铵化后效力完全丧失。（5）维拉帕米衍生物的生物活性与分配系数P之间未获得显著相关性。（6）对A组维拉帕米衍生物（= C附近苯环的不同取代）的Hansch分析表明，生物活性的变化可以与哈米特常数和摩尔体积的组合最佳相关。对B组（=异丙基交换）的Hansch分析得出结论，疏水效应是异丙基取代基影响的原因。
