(N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human platelets.

Journal of Thrombosis and Haemostasis : JTH
D M BourdonT Kendall Harden

Abstract

Adenosine diphosphate (ADP) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq-coupled P2Y1 receptor and the Gi-coupled P2Y12 receptor. We recently described the synthesis and P2Y1 receptor-specific agonist activity of (N)-methanocarba-2MeSADP (MRS2365). Consequences of selective activation of the P2Y1 receptor by MRS2365 have been further examined in human platelets. Whereas MRS2365 alone only induced shape change, addition of MRS2365 following epinephrine treatment, which activates the Gi/z-linked, alpha2A-adrenergic receptor, resulted in sustained aggregation that was indistinguishable from that observed with ADP. Conversely, the platelet shape change promoted by ADP in the presence of the GPIIb/IIIa antagonist eptifibatide was similar to that promoted by MRS2365. Preaddition of the high affinity P2Y1 receptor antagonist MRS2500 inhibited the effect of MRS2365, whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365-induced shape change. Preactivation of the P2Y1 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20-fold rightward shift in the concentration effect curve of ADP. Th...Continue Reading

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Citations

Apr 13, 2011·Purinergic Signalling·Kenneth A JacobsonStefano Costanzi
Jul 3, 2010·Drug Discovery Today·Kenneth A Jacobson, Jean-Marie Boeynaems
Jan 18, 2008·Biochemical Pharmacology·Zhan-Guo GaoKenneth A Jacobson
May 19, 2011·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·D GallegoM Jimenez
Jan 14, 2010·Biochemical Pharmacology·Ramachandran BalasubramanianKenneth A Jacobson
Mar 15, 2018·European Journal of Pharmacology·Richard T AmisonSimon C Pitchford
Jun 25, 2009·Journal of Cell Science·Ivette GrimmHerbert Zimmermann

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