The hypolipidemic drug metabolites nafenopin‐CoA and ciprofibroyl‐CoA are competitive P2Y₁ receptor antagonists

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 ATPgated currents evoked by the human P2Y 1 but not the P2Y 2 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 cipro¢brate, two clinically relevant hypolipidemic drugs, increased 13 and three-fold the potency of CoA-SH, respectively. The K B s of nafenopinCoA and cipro¢broyl-CoA were 58 and 148 nM, respectively; the slopes of the Schild plots were unitary. Neither 100 W WM nafenopin nor cipro¢brate alone altered the P2Y 1 receptor activity. Neither CoA-SH nor cipro¢broyl-CoA antagonized the rat P2X 2 or the P2X 4 nucleotide receptors nor interacted with the 5-HT 2A=C receptors. The bulky drug CoA-SH derivatives identify a hydrophobic pocket, which may serve as a potential target for novel selective P2Y 1 antagonists. ß

Molecular Recognition at Purine and Pyrimidine Nucleotide (P2) Receptors

“…A dipeptide conjugate of adenosine 49a was found to antagonize hP2Y 1 receptor responses with a K B value of 4.0 μM [49]. Metabolites of hypolipidemic drugs, such as the coenzyme A conjugate of nafenopin 49b, were found to act as P2Y 1 receptor antagonists [55]. 49b displayed a K B value of 58 nM at the human P2Y 1 receptor.…”

Antagonism of P2Y1‐induced vasorelaxation by acyl CoA: a critical role for palmitate and 3′‐phosphate

“…PaCoA produced concentration–dependent inhibition of ADP‐evoked relaxation of the rat thoracic aorta, and its effects were reversible, as described at recombinant P2Y 1 receptors in Xenopus oocytes (Coddou et al ., ). PaCoA had no direct effect on the rat thoracic aorta, and was more potent than CoA and acetyl CoA as an antagonist at P2Y 1 receptors; indeed, 10 μM PaCoA caused an approximately 330‐shift of ADP‐evoked relaxations, while acetyl CoA at the same concentration produced a fivefold shift and CoA was ineffective.…”

Signalling functions of coenzyme A and its derivatives in mammalian cells

“…In contrast, a handful of papers have been published to date on extracellular signalling by CoA/acyl-CoA implicated mainly in the regulation of platelet aggregation and vasoconstriction [20][21][22][23].…”

“…A few years later, Coddou et al [22] investigated the effect of hypolipidemic drug metabolites of CoA (nafenopin-CoA and ciprofibroyl-CoA) on the function of P2Y 1 receptors expressed in Xenopus laevis oocytes. In the course of their study, they found that nafenopin-CoA and ciprofibroylCoA, as well as palmitoyl-CoA, effectively antagonized the effect of ATP on Cl − currents mediated by P2Y 1 receptors in oocytes.…”