Kunapuli Satya P, Ding Zhongren, Dorsam Robert T, Kim Soochong, Murugappan Swaminathan, Quinton Todd M
Department of Physiology, Temple University Medical School, Philadelphia, PA 19140, USA.
Curr Pharm Des. 2003;9(28):2303-16. doi: 10.2174/1381612033453947.
Platelet P2 receptors--P2Y1, P2Y12, and P2X1--constitute the means by which adenine nucleotides can activate platelets. Coactivation of the Galphaq-coupled P2Y1 and Galphai2-coupled P2Y12 receptors is necessary for ADP-mediated platelet activation, which forms the basis of using P2 antagonists as antithrombotic drugs. P2Y1 receptor antagonists inhibit platelet activation, while P2Y1 knockout mice show longer bleeding times than normal mice but few other problems; however, its ubiquitous expression in other tissues renders P2Y1 questionable as an antithrombotic target. The P2Y12 receptor is expressed nearly exclusively in platelets and brain, making it an attractive antithrombotic target. Antagonists for the P2Y12 receptor have been developed that either require metabolic activation to covalently inhibit P2Y12 and are irreversible, or simply are competitive in nature and thus reversible. Ticlopidine and clopidogrel are irreversible P2Y12 antagonists and have been repeatedly proven as clinical antithrombotic agents. In addition, a recently reported P2Y12 antagonist, CS-747, shows promise as a future antithrombotic drug. The AR-C series of compounds represent reversible P2Y12 antagonists and have been used extensively to characterize the function of P2Y12 in platelets. Clinical studies show that AR-C69931MX is as effective as clopidogrel; furthermore, the combination of AR-C69931MX (cangrelor) and clopidogrel confers greater antagonism of P2Y12 than either antagonist alone. The P2X1 receptor is a calcium channel that functions to potentiate agonist-induced platelet shape change, and its inhibition or loss has little if any effect on hemostasis. A combination of P2Y1 and P2Y12 antagonists may represent an additional course of antithrombotic treatment.
血小板P2受体——P2Y1、P2Y12和P2X1——构成了腺嘌呤核苷酸激活血小板的途径。Gαq偶联的P2Y1和Gαi2偶联的P2Y12受体的共同激活是ADP介导的血小板激活所必需的，这构成了使用P2拮抗剂作为抗血栓药物的基础。P2Y1受体拮抗剂抑制血小板激活，而P2Y1基因敲除小鼠的出血时间比正常小鼠长，但几乎没有其他问题；然而，它在其他组织中的广泛表达使得P2Y1作为抗血栓靶点存在疑问。P2Y12受体几乎只在血小板和大脑中表达，使其成为一个有吸引力的抗血栓靶点。已开发出P2Y12受体拮抗剂，它们要么需要代谢激活以共价抑制P2Y12且不可逆，要么本质上只是竞争性的，因此是可逆的。噻氯匹定和氯吡格雷是不可逆的P2Y12拮抗剂，已多次被证明是临床抗血栓药物。此外，最近报道的一种P2Y12拮抗剂CS - 747有望成为未来的抗血栓药物。AR - C系列化合物代表可逆的P2Y12拮抗剂，已被广泛用于表征P2Y12在血小板中的功能。临床研究表明，AR - C69931MX与氯吡格雷一样有效；此外，AR - C69931MX（坎格雷洛）和氯吡格雷联合使用对P2Y12的拮抗作用比单独使用任何一种拮抗剂都更强。P2X1受体是一种钙通道，其作用是增强激动剂诱导的血小板形状变化，对其抑制或缺失对止血几乎没有影响。P2Y1和P2Y12拮抗剂的联合使用可能代表抗血栓治疗的另一种方案。
