Activity of dihydrothienopyridine S312 enantiomers on L-type Ca2+ channels in isolated rat aorta and cerebral microvessels
(1993) European Journal of Pharmacology — Vol. 231, n° 3, p. 435-442 (1993)
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- The activity of the two enantiomers of the dihydrothienopyridine S312 was characterized in isolated rat aorta and cerebral microvessels. The interaction of S312 with 1,4-dihydropyridine and phenylalkylamine binding sites was also investigated in depolarized rat cerebral microvessels and in membranes from rat ileum. Both S-(+)-S312 and R-(-)-S312 dose dependently inhibited KCl-evoked contraction of the rat aorta, with IC50 values of 0.14 (0.13-0.16) and 2.98 (2.67-3.33) nM, respectively. When the aorta was preincubated with S-(+)-S312 in a depolarizing medium, the inhibitory effect was significantly increased, but this increased inhibition was not reversed by incubation in physiological medium. The effect of R-(-)-S312 was not affected by preincubation in a depolarizing medium. In rat cerebral microvessels, S-(+)-S312 inhibited the KCl-induced contraction and KCl-stimulated Ca2+ influx with similar potency. [3H](+)-PN 200-110 specific binding was competitively displaced by the two enantiomers in depolarized cerebral microvessels. The calculated Ki values were 0.12 nM for S-(+)-S312 and 2.4 nM for R-(-)-S312. Only 20% of [3H]D888 specific binding in rat ileum membranes was displaced by S-(+)-S312. The dissociation rate of [3H]D888 was markedly decreased by S-(+)-S312, and this allosteric interaction was significantly more marked than with nitrendipine. It is concluded that the dihydrothienopyridine S312 could interact with Ca2+ channels in a manner different to that of genuine dihydropyridines.
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Dessy, C., Salomone, S., Morel, N., & Godfraind, T. (1993). Activity of dihydrothienopyridine S312 enantiomers on L-type Ca2+ channels in isolated rat aorta and cerebral microvessels. European Journal of Pharmacology, 231(3), 435-442. https://doi.org/10.1016/0014-2999(93)90121-W (Original work published 1993)