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

FEBS Letters

Coddou, Claudio²  Huidobro-Toro, J.Pablo²  Boyer, José Luis¹  Loyola, Gloria²  Bronfman, Miguel² 

[1] Inspire Pharmaceuticals, Inc., Durham, NC, USA;Centro de Regulación Celular y Patologı́a, Instituto MIFAB, Departamentos de Fisiologı́a y Biologı́a Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile

关键词: P2Y1 receptor antagonists;    Acyl-CoA derivatives;    Palmitoyl-CoA;    Fibrates;    Hypolipidemic drugs;    Nafenopin-CoA;    Ciprofibroyl-CoA;    Competitive antagonism;   

DOI  :  10.1016/S0014-5793(03)00044-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 K _Bs of nafenopin-CoA and ciprofibroyl-CoA were 58 and 148 nM, respectively; the slopes of the Schild plots were unitary. Neither 100 μM 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-HT_2A/C receptors. The bulky drug CoA-SH derivatives identify a hydrophobic pocket, which may serve as a potential target for novel selective P2Y₁ antagonists.

【 授权许可】

Unknown