Mannhold R, Bayer R, Ronsdorf M, Martens L
Arzneimittelforschung. 1987 Apr;37(4):419-24.
In the present study quantitative structure-activity relationships (QSAR) for the vasodilator properties of verapamil have been derived: Potency of ring-varied verapamil congeners on the phasic and tonic component of K+-contractures has been measured in aortic rings of the cat. Potency of verapamil derivatives on the phasic component significantly correlates with lipophilic properties of the compounds. Inhibition of the tonic component best correlates with a parameter combination of steric and electronic properties (MV, sigma). These results contrast with investigations with dihydropyridine derivatives where identical SAR have been found for both response components. Furthermore, SAR analyses yield disparate results in comparison to investigations in heart muscle where primarily electronic and secondarily steric parameters best explain the potency of verapamil derivatives. The postulate of chemically differing binding sites for verapamil congeners in heart and smooth muscle is substantiated by calculating binding energies to the hypothetical binding site arginine. While negative inotropic potency of verapamil derivatives significantly correlates with binding energy to the model binding site arginine, this correlation fails in case of aortic ring. These results obtained for verapamil congeners contrast with observations with dihydropyridine derivatives where the chemistry of binding sites in heart and smooth muscle seems to be identical.
在本研究中，已得出维拉帕米血管舒张特性的定量构效关系（QSAR）：在猫的主动脉环中测量了环变体维拉帕米同系物对K⁺收缩的时相和张力成分的效力。维拉帕米衍生物对时相成分的效力与化合物的亲脂性显著相关。对张力成分的抑制作用与空间和电子性质的参数组合（MV，σ）最相关。这些结果与二氢吡啶衍生物的研究结果形成对比，在二氢吡啶衍生物的研究中，两个反应成分都发现了相同的构效关系。此外，与心肌研究相比，构效关系分析得出了不同的结果，在心肌研究中，主要是电子参数，其次是空间参数，最能解释维拉帕米衍生物的效力。通过计算与假设结合位点精氨酸的结合能，证实了维拉帕米同系物在心脏和平滑肌中具有化学性质不同的结合位点这一假设。虽然维拉帕米衍生物的负性肌力效力与模型结合位点精氨酸的结合能显著相关，但在主动脉环的情况下，这种相关性不成立。维拉帕米同系物的这些结果与二氢吡啶衍生物的观察结果形成对比，在二氢吡啶衍生物中，心脏和平滑肌中结合位点的化学性质似乎是相同的。
