Platelets ADP receptors

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Conley, P. B., Jantzen, H. M., Vincent, D., et al. (2000) Molecular identification of the platelet ADP receptor targeted by antithrombotic drugs. Blood. 96, 222A. 

Pharmacology Clopidogrel is a thienopyridine derivative, chemically related to ticlopidine, that inhibits platelet aggregation. It acts by irreversibly modifying the platelet ADP receptor. Conseguently, platelets exposed to clopidogrel are affected for the remainder of their lifespan. 

Hollopeter G, Jantzen HM, Vincent D et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409 202-7 Holton FA, Holton P (1953) The possibility that ATP is a transmitter at sensory nerve endings. J Physiol 119 50P—51P... 

Foster CJ, Prosser DM, Agans JM, et al. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 2001 107 1591-1598. 

Savi P Labouret C, Delesque N, Guette p LupkerJ, HerbertJM. P2y( 12), a new platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Commun 2001 283 379-383. 

There are a number of additional targets that may lead to effective antithrombotic therapy in ACS. In terms of anticoagulants, the concepts of agents that have dual inhibitor sites such as the one we find in heparin but that lack in some of its undesirable qualities could be very useful. The same concept may apply to drugs that have both anticoagulant and antiplatelet properties, It is quite probable that inhibitors of tissue factor as well as of the platelet ADP receptor when combined with aspirin might be very effective. An ability to block the feedback action of the polyphosphates released from platelets upon activation is also an attractive aim (Fig. 3),... 

Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409 202-207... 

Figure 20.5 Metabolic activation of clopidogrel (12) in humans. A small part of a dose is activated by CYP3A to 2-oxo-clopidogrel (13), followed by hydrolytic ring opening to the active agent, a highly reactive thiol metabolite (14) that irreversibly antagonizes platelet ADP receptors via a covalent S-S bridge [31, 32].

When 2-aminobenzothiazoles 204 (R = H, OMe, OEt, F, Cl, NO2, SO2NH2) are treated with 2 molar equiv of chlorosulfonylacetyl chloride and base, the fused 4//-l-thia-2,4-diazine 1,1-dioxides 205 result, which are of interest as potential platelet ADP receptor inhibitors (Equation 44) <1999W09939525>. 

Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001 86 222-232. 

There are three important ADP receptors on the platelet surface (16). The P2X, inotrophic receptor is responsible for rapid influx of calcium into the cytosol. The P2Y, receptor mediates mobilization of calcium through activation of PLC and shape change. The P2Y,2 receptor is coupled to adenyl cyclase inhibition mediated by a G-protein with subsequent decrease in the cAMP The decrease in cAMP stimulates dephosphorylation of VASP that is closely correlated with the GPIIb/llla activation. 

Geiger J, Brich J, Honing-Liedl M, et al. Specific impairment of human platelet P2YAC ADP receptor-mediated signalling by the antiplatelet drug Clopidogrel. Arterioscler Thromb Vase Biol 1999 19 2007-201 I. 

Dorsam RT Tuluc M, Kunapuli SR Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets. J Thromb FHaemost 2004 2 804-812. 

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