Pharmacology of A-216546:: a highly selective antagonist for endothelin ETA receptor
Pharmacology of A-216546:: a highly selective antagonist for endothelin ETA receptor
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DOI：
10.1016/s0014-2999(98)00891-7
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发表时间：
1999-02-05
影响因子：
5
通讯作者：
Opgenorth, TJ
中科院分区：
文献类型：
--
作者：
Wu-Wong, JSR;Dixon, DB;Opgenorth, TJ
内皮素是一种由21个氨基酸组成的多肽，与内皮素ETA和ETB受体结合后发挥作用，参与多种疾病的发病机制。在本文中，我们描述了A-216546（[2S-（2，2-二甲基戊基）-4S-（7-甲氧基-1，3-苯并二氧杂环戊烯-5-基）-1-（N，N-二（正丁基）氨基羰基甲基）-吡咯烷-3 R-羧酸）的药理学特征，这是一种对内皮素ETA受体具有> 25，000倍选择性的强效拮抗剂。A-216546竞争性抑制[I-125]内皮素-1与克隆人内皮素ETA和ETB受体的结合，Ki分别为0.45和13，000 nM，并阻断内皮素-1诱导的花生四烯酸释放和磷脂酰肌醇水解，IC 50分别为0.59和3 nM。在离体血管中，A-216546抑制内皮素ETA受体介导的内皮素-1诱导的血管收缩和内皮素ETB受体介导的sarafotoxin 6c诱导的血管收缩，pA（2）分别为8.29和4.57。A-216546可在大鼠、犬和猴中经口给药。在体内，A-216546以剂量依赖性方式阻断清醒大鼠中内皮素-1诱导的加压反应。最大抑制在给药后至少8 h保持恒定。总之，A-216546是一种有效的、高内皮素ETA受体选择性的口服拮抗剂，可用于治疗内皮素-1介导的疾病。(C)1999 Elsevier Science B. V.保留所有权利。
Endothelins, 21-amino acid peptides involved in the pathogenesis of various diseases, bind to endothelin ETA and ETB receptors to initiate their effects. Here, we characterize the pharmacology of A-216546 ([2S-(2,2-dimethylpentyl)-4S-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl) aminocarbonylmethyl)-pyrrolidine-3 R-carboxylic acid), a potent antagonist with > 25,000-fold selectivity for the endothelin ETA receptor. A-216546 inhibited [I-125]endothelin-1 binding to cloned human endothelin ETA and ETB receptors competitively with K-i of 0.45 and 13,000 nM, and blocked endothelin-1-induced arachidonic acid release and phosphatidylinositol hydrolysis with IC50 of 0.59 and 3 nM, respectively. In isolated vessels, A-216546 inhibited endothelin ETA receptor-mediated endothelin-l-induced vasoconstriction, and endothelin ETB receptor-mediated sarafotoxin 6c-induced vasoconstriction with pA(2) of 8.29 and 4.57, respectively. A-216546 was orally available in rat, dog and monkey. In vivo, A-216546 dose-dependently blocked endothelin-1-induced presser response in conscious rats. Maximal inhibition remained constant for at least 8 h after dosing. In conclusion, A-216546 is a potent, highly endothelin ETA receptor-selective and orally available antagonist, and will be useful for treating endothelin-1-mediated diseases. (C) 1999 Elsevier Science B.V. All rights reserved.