FEBS Letters | |
The hypolipidemic drug metabolites nafenopin‐CoA and ciprofibroyl‐CoA are competitive P2Y1 receptor antagonists | |
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-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.
【 授权许可】
Unknown
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