QSAR of binding of dihydropyridine-type calcium antagonists to their receptor on ileal smooth muscle preparations

Abstract

Quantitative structure-activity analysis (Hansch analysis) is applied to elucidate the structural requirement for the binding of dihydropyridine-type calcium antagonists (DHPs) to their receptor in the guinea-pig ileal muscle preparations. It is found that various steric (B1, L), electronic (σ) and hydrophobic (π) parameters or their combinations correlate well with the potency of various DHPs to inhibit the binding of [3H]nitrendipine to the microsomal preparations of the guinea-pig ileal muscle. The potency of DHPs increases with the minimum width (B1) of substituent at ortho- or meta-positions, but decreases with the increase in the length of substituent at the meta-position. The potency of DHPs decreases with the increase in both minimum width or length of substituent at the para-position and the optimal values were found to be those for hydrogen. The hydrophobicity (π) of substituents at different positions in the 4-phenyl ring affects the potency differently, indicating that a different environment exists around each position at the binding site. From the slopes of the π variable in the regression equations, it is concluded that the receptive environment of the ortho-position of the 4-phenyl ring of DHPs is lipophilic, and for that of the para-position hydrophilic. A good correlation is also observed between the Hammett electronic parameter (σ) and biological activity of meta-substituted DHPs. It is suggested that in the binding of the substituted 4-phenyl DHPs to their receptor, both electronic and hydrophobic interactions should be considered.