Effect of S-312, a New Calcium Channel Blocker, on the 1,4-Dihydropyridine Binding Sites in Porcine Basilar Blood Vessels and Rat Aortic Smooth Muscle Cells

Abstract

We examined the interaction of two isomers of S-312, a new calcium channel blocker with a bicyclic dihydrothienopyridine structure, with 1,4-dihydropyridine binding sites. Specific bindings of [3H]nitrendipine and (+)-[3H]PN200-110 in membranes prepared from porcine basilar blood vessels were saturable, reversible, and stereoselective, and had high affinities. The binding properties were very similar to those in membranes from other tissues such as the aorta, myocardium, and cerebral cortex. 1,4-Dihydropyridine calcium channel blockers competed for each radioligand binding in the order of: nisoldipine = nicardipine = S-(+)-S-312 > nifedipine > R-(—)-S-312. S-(+)-S-312 caused a decrease in the Kd values for both radioligands without changing the maximal binding capacity. 1,4-Dihydropyridines inhibited the high K+-induced increase in cytosolic free Ca2+ concentration in rat aortic smooth muscle A7r5 cells. 5-(+)-S-312 was 3.3-4.9 times more potent than nicardipine or nisoldipine in inhibiting the Ca2+ increase, although S-(+)-S-312 bound to A7r5 cells with almost the same affinity. These and earlier findings show that S-(+)-S-312 exerts effects more potent than expected from the affinity for [3H]nitrendipine or (+)-[3H]PN200-110 binding sites. This was the case with R-(—)-S-312. These dihydrothienopyridine derivatives appear to interact with the Ca2+ channel in a manner slightly different from the conventional 1,4-dihydropyridines.