The hypolipidemic drug metabolites nafenopin‐CoA and ciprofibroyl‐CoA are competitive P2Y1 receptor antagonists
The hypolipidemic drug metabolites nafenopin‐CoA and ciprofibroyl‐CoA are competitive P2Y1 receptor antagonists
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降血脂药物代谢物萘诺平-CoA 和环丙纤维酰-CoA 是竞争性 P2Y1 受体拮抗剂
DOI：
10.1016/s0014-5793(03)00044-9
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发表时间：
2003
期刊：
影响因子：
3.5
通讯作者：
J. Huidobro‐Toro
中科院分区：
文献类型：
--
作者：
C. Coddou;G. Loyola;J. Boyer;M. Bronfman;J. Huidobro‐Toro
辅酶A（CoA-SH），内源性和药物衍生的CoA衍生物作为非洲爪蟾卵母细胞中表达的P2 Y受体的推定拮抗剂进行了测试，该方法用于确定钙激活的氯电流，这些受体激活的指标。CoA-SH可逆地拮抗人P2 Y1受体诱发的ATP门控电流，并呈浓度依赖性。棕榈酰-CoA作为拮抗剂的效力是CoA-SH的四倍，而棕榈酰-肉毒碱是无活性的，突出了CoA-SH部分在拮抗作用中的作用。两种临床相关的降血脂药物那非诺平和环丙贝特的CoA衍生物分别使CoA-SH的效力增加了13倍和3倍。那非那平-CoA和环丙纤维酰-CoA的KB分别为58和148 nM; Schild图的斜率为单一的。单独使用100 μM萘芬诺平或环丙贝特均不能改变P2 Y1受体活性。CoA-SH和ciprofibroyl-CoA均不拮抗大鼠P2 X2和P2 X4核苷酸受体，也不与5-HT 2A/C受体相互作用。庞大的药物CoA-SH衍生物确定了一个疏水口袋，这可能是一个潜在的目标，为新的选择性P2 Y1拮抗剂。
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 P2Y1but not the P2Y2receptor. 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 μM nafenopin nor ciprofibrate alone altered the P2Y1receptor activity. Neither CoA-SH nor ciprofibroyl-CoA antagonized the rat P2X2or the P2X4nucleotide receptors nor interacted with the 5-HT2A/Creceptors. The bulky drug CoA-SH derivatives identify a hydrophobic pocket, which may serve as a potential target for novel selective P2Y1antagonists.
三磷酸腺苷对人类 P2Y1 受体的激动作用。
影响因子：
3.6
作者：
Palmer,RK;Boyer,JL;Schachter,JB;Nicholas,RA;Harden,TK
通讯作者：
Harden,TK