1,4-Dihydropyridines, a new class of platelet-activating factor receptor antagonists: in vitro pharmacologic studies.

PCA 4233 [2-(phenylthio)ethyl-5-ethoxycarbonyl-2,4,6-trimethyl- 1,4-dihydropyridine-3-carboxylate] and PCA 4248 [2-(phenylthio) ethyl-5-methoxycarbonyl-2, 4, 6-trimethyl-1, 4-dihydropyridine-3-carboxylate], two compounds developed from a series of 1,4-dihydropyridines that lack pharmacologic effects on voltage-operated calcium channels, were found to block selectively rabbit operated calcium channels, were found to block selectively rabbit and human platelet aggregation and secretion, and binding of [3H]-labeled platelet-activating factor (PAF) to human platelet and polymorphonuclear PAF receptors. Rabbit platelet aggregation was tested with 1.9 nM PAF, i.e., a concentration producing maximal response, and was completely blocked with 10 microM PCA 4233 and 3 microM 4248 (IC50 values, 2.55 and 1.05 microM, respectively). Human platelet aggregation in platelet-rich plasma was studied with 1 microM PAF, a concentration that caused a response comparable with that of 1.9 nM PAF in rabbit platelets. The IC50 of PCA 4248 for ATP release under these conditions was 3.6 microM. PCA 4248 behaved as a competitive and selective antagonist in [3H]serotonin secretion studies on rabbit platelets, since it displaced rightwards log dose-response curves and lacked any effect on thrombin- and ionophore A23187-induced platelet secretion. A pA2 value of 7.5 was obtained from Schild plots on [3H]serotonin secretion studies. PCA 4248 also produced a dose-dependent inhibition of [3H]PAF binding to human platelets and to human polymorphonuclear leukocytes. These data indicate that PCA 4233 and PCA 4248 belong to a new class of selective PAF-receptor antagonists.