Stereoselectivity at the Calcium Channel

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Abstract
The stereoisomers of the new dihydropyri-dine derivative 202–791 [isopropyl 4-(2,1,3-benzoxadi-azol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecar-boxylate] were synthesized separately and tested on isolated rabbit aortic rings for effects on depolarization-induced contraction and depolarization-stimulated uptake of 45Ca2+. The racemic mixture enhanced contraction of rabbit aortic rings at low levels of depolarization but inhibited contraction and 45Ca2+ uptake at high levels of depolarization. The IC50 values were 2.0 × 10−7 and 1.7 × 107M, respectively. The R enantiomer inhibited contraction and 45Ca2+ uptake with IC50 values of 3.2 × 10−8 and 4.3 × 10−8M, respectively. This compound showed no stimulant activity. By contrast, the S enantiomer of 202–791 shifted the concentration-response curve for depolarization-induced contraction in an almost parallel fashion to the left, thus enhancing contraction. The EC50 value for this effect at a KCl concentration of 16 mM was 1.8 × 10−7M. This compound enhanced 45Ca2+ uptake concentration dependently at all levels of depolarization tested. Thus, the stereoisomers of a dihydropyridine derivative may behave as a calcium entry blocker or a calcium entry enhancer on vascular smooth muscle, depending only on the stereochemistry. If asymmetric compounds elicit effects suggesting a dualistic action at the calcium channel, then the stereoisomers should be prepared.