Effects of phosphate-modified analogs of adenosine 5′-diphosphate and adenosine 5′-triphosphate at P2T-purinoceptors mediating human platelet activation by ADP

• Published in: Drug development research Vol. 37; no. 4; pp. 212 - 222
• Main Authors: Cusack, Noel J., Pettey, Caroline J.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.04.1996; Wiley-Liss
• Subjects: adenylate cyclase; ADP analogs; ATP analogs; Biological and medical sciences; Blood coagulation. Blood cells; cyclic AMP; Fundamental and applied biological sciences. Psychology; human blood platelets; Molecular and cellular biology; P2T-purinoceptor agonists; P2T-purinoceptor antagonists; P2T-purinoceptors; Platelet; Aggregation; Human; Platelet; Structure activity relation; Analog; P2 Purinergic receptor; Activation; ADP; ATP; In vitro; Biological activity
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/(SICI)1098-2299(199604)37:4<212::AID-DDR3>3.0.CO;2-O

Adenosine 5′‐diphosphate (ADP) induces human platelet aggregation and inhibits stimulated adenylate cyclase by an action at P2T‐purinoceptors. Both of these effects of ADP are inhibited competitively by ATP. Structure‐activity relationships for phosphate‐modified analogs of ADP and adenosine 5′‐triphosphate (ATP) were studied by testing their effects on human platelet activation. Of the ADP analogs, only β,γ‐imido‐ADP (AMPNHP) induced platelet aggregation, but was a weak partial agonist (pA50 4.53). ADP‐induced platelet aggregation was antagonized noncompetitively by β,γ‐methylene‐ADP (AMPCP) (pA2 3.2), β,γ‐ethylene‐ADP (AMPCCP) (pA2 4.42), and β,γ‐difluoromethylene‐ADP (AMPCF2P) (pA2 4.77), and competitively by β,γ‐dichloromethylene‐ADP (AMPCCl2P) (pA2 4.68). None of the ADP analogs inhibited prostaglandin E1 (PGE1)‐stimulated adenylate cyclase, and ADP‐induced inhibition of PGE1‐stimulated adenylate cyclase was unaffected by AMPNHP, AMPCP, or AMPCCP (100 μM), but was antagonized by AMPCF2P (pA2 4.36) and AMPCCl2P (4.24). ADP‐induced platelet aggregation was antagonized competitively by the ATP analogs β,γ‐difluoromethylene‐ATP (AMP‐PCF2P) (pA2 4.55), β,γ‐dichloromethylene‐ATP (AMP‐PCCl2P) (pA2 4.42), and β,γ‐imido‐ATP (AMP‐PNHP) (pA2 4.32) and non‐competitively by 2‐methylthio‐β,γ‐methylene‐ATP (2‐MeS‐AMP‐PCP), 2‐methylthio‐β,γ‐difluoromethylene‐ATP (2‐MeS‐AMP‐PCF2P), and 2‐methylthio‐β,γ‐dichloromethylene‐ATP (2‐MeS‐AMP‐PCCl2P). In summary, agonist activity at the human platelet P2T‐purinoceptor was extremely sensitive to alterations to the diphosphate chain of ADP, and only AMPNHP induced platelet aggregation. Increasing the electronegativity of the methylene group by halogen substitution increased the antagonist potency of the ADP analog AMPCP but resulted in little or no change in the antagonist potencies of the ATP analogs AMP‐PCP and 2‐MeS‐AMP‐PCP. © 1996 Wiley‐Liss, Inc.