Sunkel C E, de Casa-Juana M F, Santos L, Gómez M M, Villarroya M, González-Morales M A, Priego J G, Ortega M P
ALTER, S.A., Research Department, Madrid, Spain.
J Med Chem. 1990 Dec;33(12):3205-10. doi: 10.1021/jm00174a017.
A new series of 4-alkyl-1,4-dihydropyridines (1,4-DHP) were synthesized and evaluated for their ability to inhibit washed rabbit platelet aggregation induced by PAF-acether (1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glycero-3-phosphorylcholine) and to reverse PAF-induced hypotension in anesthetized rats. Additionally, compounds were evaluated for their ability to inhibit the binding of radiolabeled PAF to its receptor on rabbit platelets. Among these compounds, 6I and 6L were the most potent and specific antagonists. At concentrations up to 100 microM, neither compound 6I nor compound 6L caused platelet aggregation nor did they inhibit platelet aggregation induced by collagen or adenosine diphosphate. Compound 6L did not show in vitro calcium channel blocker activity measured on vascular smooth muscle preparations of rabbit aorta and on [3H]nitrendipine binding assays. The compound did not show any cardiovascular effects in anesthetized rat at iv doses up to 1000 micrograms/kg, and the Ki value was 568.62 nmol. These results indicate that compound 6L is a potent and specific PAF antagonist with 1,4-dihydropyridine structure but devoid of a significant cardiovascular activity related to calcium-antagonist properties.
合成了一系列新的4-烷基-1,4-二氢吡啶（1,4-DHP），并评估了它们抑制PAF-乙醚（1-O-十六烷基/十八烷基-2-O-乙酰基-sn-甘油-3-磷酸胆碱）诱导的洗涤兔血小板聚集以及逆转PAF诱导的麻醉大鼠低血压的能力。此外，还评估了这些化合物抑制放射性标记的PAF与其在兔血小板上的受体结合的能力。在这些化合物中，6I和6L是最有效和最具特异性的拮抗剂。在浓度高达100 microM时，化合物6I和化合物6L均未引起血小板聚集，也未抑制胶原蛋白或二磷酸腺苷诱导的血小板聚集。化合物6L在兔主动脉血管平滑肌制剂和[3H]尼群地平结合试验中未表现出体外钙通道阻滞剂活性。该化合物在静脉注射剂量高达1000微克/千克时，在麻醉大鼠中未表现出任何心血管作用，其Ki值为568.62纳摩尔。这些结果表明，化合物6L是一种具有1,4-二氢吡啶结构的有效且特异性的PAF拮抗剂，但缺乏与钙拮抗剂特性相关的显著心血管活性。
