Thromboxane A2

ANALGESICS,ANTIPYRETICS,ANDANTIINFLAL TATORYAGENTS] (Vol2) Thromboxane A2 [57576-52-0]... 

Thromboxane A2 is a potent platelet aggregating agent and vasodilator which undergoes rapid hydrolysis under physiological conditions (ti/2 32 sec. at pH 7 and 37°C). The synthesis of stable analogs was of interest for biological studies of this potent but evanescent prostanoid. 

The synthesis of thromboxane Bj, the hydrolytic deactivation product of thromboxane A2, provided this material for studies of metabolism and bioactivity, and also for the development of a radioimmunassay. Two different synthetic routes were developed. 

The formation of a platelet aggregate requires the recruitment of additional platelets from the blood stream to the injured vessel wall. This process is executed through a variety of diffusible mediators which act through G-protein-coupled receptors. The main mediators involved in this process are adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin (factor Ila). These mediators of the second phase of platelet activation are formed in different ways. While ADP is secreted from platelets by exocytosis, the release of TXA2 follows its new formation in activated platelets. Thrombin can be formed on the surface of activated platelets (see Fig. 2). 

CYP5 synthesizes thromboxane A2, a fatty acid in the arachidonic acid cascade that causes platelet aggregation. Aspirin prevents platelet aggregation because it blocks the cyclooxygenases COX1 and COX2 which catalyze the initial step of the biotransformation of arachidonic acid to thromboxane and prostaglandins. 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

In the first total synthesis of thromboxane A2, lactone 340 is opened by potassium trimethylsilanolate 97 to give the potassium salt 341 [120]. The potassium salt of the methoxymethyl ether of salicylic acid is prepared likewise [121], as are... 

CoUagen-induced activation of a platelet phospholipase A2 by increased levels of cytosolic Ca results in hberation of arachidonic acid from platelet phospho-hpids, leading to the formation of thromboxane A2 (Chapter 23), which in turn, in a receptor-mediated fashion, can further activate phospholipase C, promot-ing platelet aggregation. 

Aspirin is an important antiplatelet drug that acts by inhibiting production of thromboxane A2. 

Lelcuk, S., Alexander, F., Kobzik, L., Valeri, C.R., Shepro, D. and Hechtman, H.B. (1985). Prostaglandins and thromboxane A2 moderate post-ischaemic renal failure. Surgery 98, 207-212. 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

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