Ortega M P, García M C, Gijón M A, de Casa-Juana M F, Priego J G, Sanchez Crespo M, Sunkel C
Departamento de Investigación, ALTER S.A., Madrid, Spain.
J Pharmacol Exp Ther. 1990 Oct;255(1):28-33.
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.
PCA 4233 [2-(苯硫基)乙基-5-乙氧羰基-2,4,6-三甲基-1,4-二氢吡啶-3-羧酸酯]和PCA 4248 [2-(苯硫基)乙基-5-甲氧羰基-2,4,6-三甲基-1,4-二氢吡啶-3-羧酸酯]，是从一系列对电压门控钙通道无药理作用的1,4-二氢吡啶类化合物中开发出来的两种化合物，它们被发现能选择性地阻断兔和人血小板的聚集、分泌以及[3H]标记的血小板活化因子（PAF）与人血小板和多形核白细胞PAF受体的结合。兔血小板聚集实验采用1.9 nM PAF进行测试，即产生最大反应的浓度，10 μM的PCA 4233和3 μM的4248可完全阻断该反应（IC50值分别为2.55和1.05 μM）。富含血小板血浆中的人血小板聚集实验采用1 μM PAF进行研究，该浓度在兔血小板中引起的反应与1.9 nM PAF相当。在这些条件下，PCA 4248对ATP释放的IC50为3.6 μM。在兔血小板的[3H]5-羟色胺分泌研究中，PCA 4248表现为竞争性和选择性拮抗剂，因为它使对数剂量反应曲线右移，且对凝血酶和离子载体A23187诱导的血小板分泌无任何影响。从[3H]5-羟色胺分泌研究的Schild图中获得的pA2值为7.5。PCA 4248还对[3H]PAF与人血小板和人多形核白细胞的结合产生剂量依赖性抑制。这些数据表明，PCA 4233和PCA 4248属于一类新型的选择性PAF受体拮抗剂。
