PCA 50941, a novel Ca2+ channel agonist.

PCA 50941 is a novel 1,4-dihydropyridine derivative. Its vasoconstricting effects prompted a systematic comparison with the prototypic Ca2+ channel activator, Bay K 8644. The two compounds exhibit marked analogies and differences in their cardiovascular profiles. PCA 50941 exhibits a pronounced vascular over cardiac selectivity while Bay K 8644 has both potent vasoconstrictor effects and strong cardiac positive inotropic actions. PCA 50941 exhibits either poor positive inotropic effects (isolated guinea-pig atria) or clear negative inotropic effects (isolated perfused rat heart). Both compounds reduced by 10-40% the coronary flow in the perfused rat heart. However, PCA 50941 had slight vasoconstrictor effects in pig coronary arteries, causing their relaxation at nanomolar/micromolar concentrations; this contrasts with the almost pure, marked vasoconstrictor effects of Bay K 8644 in coronary arteries. In the rat aorta PCA 50941 exhibited a biphasic pattern of vasoconstriction and vasorelaxation, and in portal vein it markedly reduced the Ca(2+)-evoked contractions; Bay K 8644 behaved as a pure vasoconstrictor in these two preparations. It is concluded that the racemic compound, PCA 50941, exhibits different degrees of Ca2+ agonism and Ca2+ antagonism by acting upon 1,4-dihydropyridine receptors of different cardiovascular tissues. Its tissue selectivity and its prolonged duration of action give PCA 50941 a cardiovascular profile more favourable than that of other 1,4-dihydropyridine Ca2+ agonist existing to date.

Synthesis, platelet aggregation inhibitory activity, and in vivo antithrombotic activity of new 1,4-dihydropyridines.

A series of 1,4-dihydropyridines (DHP) bound to 1,2-benzisothiazol-3-ones were synthesized and evaluated for their ability to inhibit platelet aggregation induced by collagen in human platelet-rich plasma (PRP) and to protect mice against experimental thrombosis. The results showed that the compounds were in vitro inhibitors of collagen-induced platelet aggregation. Most of them were also effective in reducing mortality in the mouse antithrombotic assay. 2-(1,1,3-Trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl)ethyl 2,6-dimethyl-5-(ethoxycarbonyl)-4-methyl-1,4-dihydropyridinecarboxyla te (4A) is the most promising compound. This compound did not show any cardiovascular effects either in the anesthetized cat or in the anesthetized rat at iv doses up to 750 or 500 micrograms/kg, respectively. Likewise, antiplatelet and cardiovascular effects of compound 4A were simultaneously studied in anesthetized rats and compared with those of nitrendipine.