Interaction of the active metabolite of prasugrel, R-138727, with cysteine 97 and cysteine 175 of the human P2Y12 receptor

Journal of Thrombosis and Haemostasis

Volumn 6, Issue 11, 2008, Pages 1908-1914

  Algaier, I ^a   Jakubowski, J A ^b   Asai, F ^c   von Kügelgen, Ivar ^a  

^a UNIVERSITY OF BONN   (Germany)

^b ELI LILLY AND COMPANY   (United States)

^c DAIICHI SANKYO CO   (Japan)

Author keywords

P2Y12 receptor; Platelets; Prasugrel; Site of action; Site directed mutagenesis

Indexed keywords

2 [1 [2 CYCLOPROPYL 1 (2 FLUOROPHENYL) 2 OXOETHYL] 4 MERCAPTO 3 PIPERIDINYLIDENE]ACETIC ACID; 2 METHYLTHIOADENOSINE TRIPHOSPHATE; ACETYLCYSTEINE; ADENOSINE TRIPHOSPHATE; ALANINE; ANTITHROMBOCYTIC AGENT; CYCLIC AMP; CYSTEINE; DISULFIDE; FORSKOLIN; PRASUGREL; PURINERGIC P2Y12 RECEPTOR; R 138727; SURAMIN; THIENOPYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING SITE; CHO CELL; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; DISULFIDE BOND; DRUG MECHANISM; DRUG POTENCY; DRUG TARGETING; FEMALE; INHIBITION KINETICS; LIGAND BINDING; NONHUMAN; PREDICTION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN INTERACTION; THROMBOCYTE AGGREGATION INHIBITION; WILD TYPE;

ANIMALS; BINDING SITES; CHO CELLS; CRICETINAE; CRICETULUS; CYSTEINE; HUMANS; PIPERAZINES; PLATELET AGGREGATION INHIBITORS; RECEPTORS, PURINERGIC P2; THIOPHENES; TRANSDUCTION, GENETIC;

EID: 54149112344     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/j.1538-7836.2008.03136.x     Document Type: Article

References (21)

1. Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50: 413-92.
2. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA. International Union of Pharmacology LVIII: Update on the P2Y G protein-coupled nucleotide receptors: From molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 2006; 58: 281-341.
3. von Kügelgen I. Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther 2006; 110: 415-32.
4. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-7.
5. 12 receptor in platelet activation. J Clin Invest 2004; 113: 340-5.
6. Kulick MB, von Kügelgen I. P2Y-receptors mediating an inhibition of the evoked entry of calcium through N-type calcium channels at neuronal processes. J Pharmacol Exp Ther 2002; 303: 520-6.
7. 12 ADP-receptor. J Thromb Haemost 2004; 2: 135-46.
8. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-6.
9. Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-46.
10. Sugidachi A, Asai F, Yoneda K, Iwamura R, Ogawa T, Otsuguro K, Koike H. Antiplatelet action of R-99224, an active metabolite of a novel thienopyridine-type G(i)-linked P2T antagonist, CS-747. Br J Pharmacol 2001; 132: 47-54.
11. 12 receptor inhibitor. Thromb Haemost 2005; 94: 593-8.
12. Jakubowski JA, Payne CD, Weerakkody GJ, Brandt JT, Farid NA, Li YG, Naganuma H, Lachno DR, Winters KJ. Dose-dependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects. J Cardiovasc Pharmacol 2007; 49: 167-73.
13. Jakubowski JA, Winters KJ, Naganuma H, Wallentin L. Prasugrel: A novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev 2007; 25: 357-74.
14. Payne CD, Li YG, Small DS, Ernest CS II, Farid NA, Jakubowski JA, Brandt JT, Salazar DE, Winters KJ. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50: 555-62.
15. 12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 2003; 101: 3908-14.
16. 12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci USA 2006; 103: 11069-74.
17. 1 receptor in surface expression and activation processes. J Biol Chem 1999; 274: 14639-47.
18. 1 inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol 2007; 63: 421-30.
19. Ivanov AA, Costanzi S, Jacobson KA. Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling. J Comput Aided Mol Des 2006; 20: 417-26.
20. Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Charnigo R, Akers WS. Transitioning patients from cangrelor to clopidogrel: Pharmacodynamic evidence of a competitive effect. Thromb Res 2008; 121: 527-34.
21. Campbell CL, Berger PB, Nuttall GA, Orford JL, Santrach PJ, Oliver WC, Ereth MH, Thompson CM, Murphy MK, McGlassen DL, Schrader LM, Steinhubl SR. Can N-acetylcysteine reverse the antiplatelet effects of clopidogrel? An in vivo and vitro study. Am Heart J 2005; 150: 796-9.