title: Activity of dihydrothienopyridine S312 enantiomers on L-type Ca2+ channels in isolated rat aorta and cerebral microvessels.
abstract: 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.
authors.affiliation: Laboratoire de Pharmacologie, Université Catholique de Louvain, Bruxelles, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Dessy
authors.forename: S
authors.initials: S
authors.lastname: Salomone
authors.forename: N
authors.initials: N
authors.lastname: Morel
authors.forename: T
authors.initials: T
authors.lastname: Godfraind
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014665:Vasodilator Agents; C059447:S 312; D011189:Potassium Chloride; C038806:1,4-dihydropyridine; D002118:Calcium