title: 1,4-Dihydropyridines, a new class of platelet-activating factor receptor antagonists: in vitro pharmacologic studies.
abstract: 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.
authors.affiliation: Departamento de Investigación, ALTER S.A., Madrid, Spain.
authors.forename: M P
authors.initials: MP
authors.lastname: Ortega
authors.forename: M C
authors.initials: MC
authors.lastname: García
authors.forename: M A
authors.initials: MA
authors.lastname: Gijón
authors.forename: M F
authors.initials: MF
authors.lastname: de Casa-Juana
authors.forename: J G
authors.initials: JG
authors.lastname: Priego
authors.forename: M
authors.initials: M
authors.lastname: Sanchez Crespo
authors.forename: C
authors.initials: C
authors.lastname: Sunkel
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin / Q000378:metabolism
chemical_list: D004095:Dihydropyridines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C066024:PCA 4248; D012701:Serotonin; C066025:PCA 4233