The hypolipidemic drug metabolites nafenopin-CoA and ciprofibroyl-CoA are competitive P2Y1 receptor antagonists.
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 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 ciprofibrate, two clinically relevant hypolipidemic drugs, increased 13 and three-fold the potency of CoA-SH, respectively. The K(B)s of nafenopin-CoA and ciprofibroyl-CoA were 58 and 148 nM, respectively; the slopes of the Schild plots were unitary. Neither 100 microM nafenopin nor ciprofibrate alone altered the P2Y(1) receptor activity. Neither CoA-SH nor ciprofibroyl-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.
Coddou
Claudio
C
Centro de Regulación Celular y Patología, Instituto MIFAB, Departamentos de Fisiología y Biologi;a Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile.
Loyola
Gloria
G
Boyer
José Luis
JL
Bronfman
Miguel
M
Huidobro-Toro
J Pablo
JP
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D009255:Nafenopin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000145:classification; D058472:Receptors, Purinergic P2Y1; D014981:Xenopus
D000214:Acyl Coenzyme A; D000960:Hypolipidemic Agents; C546382:P2RY1 protein, human; C546384:P2ry1 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; C471851:ciprofibroyl-coenzyme A; D009255:Nafenopin; C051515:nafenopin-coenzyme A; D000255:Adenosine Triphosphate