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A membrane bilayer pathway model has been proposed for the interaction of dihydropyridine (DHP) calcium channel antagonists with receptors in cardiac sarcolemma (Rhodes, D.G., J.G. Sarmiento, and L.G. Herbette. 1985. Mol. Pharmacol. 27:612-623) involving drug partition into the bilayer with subsequent receptor binding mediated (though probably not rate-limited) by diffusion within the bilayer. Recently, we have characterized the partition step, demonstrating that DHPs reside, on a time-average basis, near the bilayer hydrocarbon core/water interface. Drug distribution about this interface may define a plane of local concentration for lateral diffusion within the membrane. The studies presented herein examine the diffusional dynamics of an active rhodamine-labeled DHP and a fluorescent phospholipid analogue (DiIC16) in pure cardiac sarcolemmal lipid multibilayer preparations as a function of bilayer hydration. At maximal bilayer hydration, the drug diffuses over macroscopic distances within the bilayer at a rate identical to that of DiI (D = 3.8 X 10(-8) cm2/s), demonstrating the overall feasibility of the membrane diffusion model. The diffusion coefficients for both drug and lipid decreased substantially as the bilayers were dehydrated. While identical at maximal hydration, drug diffusion was significantly slower than that of DiIC16 in partially dehydrated bilayers, probably reflecting differences in mass distribution of these probes in the bilayer.

A series of isobutyl methyl 2,6-dimethyl-4-(X-substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylates (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, 4-F, 2-CF3, 3-CF3, and 4-Cl) related to and including nisoldipine (X = 2-NO2) has been synthesized, their solid-state structures determined by X-ray analysis (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, and 4-F), and their pharmacologic activities determined, as the racemic compounds, against [3H]nitrendipine binding and K+-depolarization-induced tension responses in intestinal smooth muscle as measures of Ca2+ channel antagonist activity. Comparisons of structure are presented to previously analyzed 1,4-dihydropyridines. The degree of 1,4-dihydropyridine ring puckering is dependent on the nature and position of the phenyl ring substituent and the adopted interring conformation. Different ester substituents affect 1,4-dihydropyridine ring puckering to a small extent in most cases. Pharmacologic and radioligand binding activities for the nine compounds studied show a parallel dependence on phenyl ring substituent, but the compounds are approximately 10-fold more active in the radioligand binding assay than in the pharmacologic assay. Consistent with a previous report for the nifedipine series (Fossheim et al. J. Med. Chem. 1982, 25, 126), pharmacologic activity increases with increasing 1,4-dihydropyridine ring planarity.

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