Calcium channel blocking properties of SM-6586 in rat heart and brain as assessed by radioligand binding assay.

The interaction of SM-6586 (methyl 1,4-dihydro-2,6-dimethyl-3-[3-(N-benzyl-N-methyl-aminomethyl)-1,2,4- oxadiazolyl-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate) with the specific binding of 3H-PN200-110 to rat heart and brain membranes was characterized and compared with those of other Ca2+ antagonists. The blockade of 3H-PN200-110 binding sites induced by nifedipine, nitrendipine and nimodipine was reversed by washing, whereas the blockade by SM-6586 was not readily reversed under these conditions. No significant difference was found in irreversibility between SM-6586 enantiomers. When rat aortic strips were pretreated with SM-6586, the contractions induced by 50 mM KCl were inhibits even though SM-6586 was not present in the extracellular medium. This residual inhibitory effect was much stronger than that of nicardipine. The inhibition of KCl-induced contractions by nifedipine and nitrendipine was easily reversed by washing. Thus, we suggest that (+)SM-6586 is a novel 1,4-dihydropyridine derivative having a very slow rate of dissociation from the binding site. This property may explain its long-lasting antihypertensive effect.