Horst Meyer

Effects of unsymmetrical ester substituted 1,4-dihydropyridine derivatives and their optical isomers on contraction of smooth muscle

SummaryThe optical isomers of two nifedipine-like 1,4-dihydropyridine derivates have been synthesised and tested in vitro. The (−)-isomer (S-configuration of both compounds) was more potent than the racemate, which in turn was more potent than the (+)-isomer (R-configuration). The S-configuration isomers are approximately ten times more potent than nifedipine, and may represent the optimal structure and configuration for binding to and inhibiting calcium channels.

QSAR-Studies in the Inotropic Action of Nifedipine-Derivatives

Among the so-called calcium-antagonists one of the most potent and commonly used compounds is nifedipine. Based on an analysis of the specific inotropic action of nifedipine exerted in cat papillary muscles we have investigated the physicochemical and steric requirements for this action. The quantitative structure-activity relationships (QSAR-studies) were realized by means of a Hansch analysis: Substituent constants, describing electronic, hydrophobic and steric properties of the nifedipine-derivatives were correlated with their biological activity (ED50-value for the negative inotropic effect). For a group of ortho-substistuted nifedipine-derivatives significant correlations were obtained mainly with steric parameters (Es, B1). The following example shows the regression analysis and the statistical data obtained with the new steric Verloop-parameter B1: log 1/ED50 =5.06 + 0,8 (± 0.15) · B1 n=8, r=0.91, T=5.28, F=27.88, P=0.0019