Abstract

Coenzyme A (CoA-SH), endogenous and drug-derived CoA-derivatives were tested as putative antagonists of P2Y receptors expressed in Xenopus laevis oocytes, a method used to determine calcium-activated chloride current, an indicator of the activation of these receptors. CoA-SH antagonized reversibly and in a concentration-dependent manner the ATP-gated currents evoked by the human P2Y1 but not the P2Y2 receptor. Palmitoyl-CoA was four-fold more potent than CoA-SH as an antagonist while palmitoyl-carnitine was inactive, highlighting the role of the CoA-SH moiety in the antagonism. The CoA derivatives of nafenopin and ciprofibrate, two clinically relevant hypolipidemic drugs, increased 13 and three-fold the potency of CoA-SH, respectively. The KBs of nafenopin-CoA and ciprofibroyl-CoA were 58 and 148 nM, respectively; the slopes of the Schild plots were unitary. Neither 100 ?M nafenopin nor ciprofibrate alone altered the P2Y1 receptor activity. Neither CoA-SH nor ciprofibroyl-CoA antagonized the rat P2X2 or the P2X4 nucleotide receptors nor interacted with the 5-HT2A/C receptors. The bulky drug CoA-SH derivatives identify a hydrophobic pocket, which may serve as a potential target for novel selective P2Y1 antagonists. © 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.