KW-3902，一种腺苷A1受体的选择性高亲和力拮抗剂。

KW-3902, a selective high affinity antagonist for adenosine A1 receptors.

作者信息

Nonaka H, Ichimura M, Takeda M, Kanda T, Shimada J, Suzuki F, Kase H

机构信息

Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.

出版信息

Br J Pharmacol. 1996 Apr;117(8):1645-52. doi: 10.1111/j.1476-5381.1996.tb15335.x.

DOI:10.1111/j.1476-5381.1996.tb15335.x

PMID:8732272

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1909575/

Abstract

We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), KW-3902 had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine (CGS21680), indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. 3. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 470 fmol mg-1 of protein) to a single class of recognition sites. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [3H]-KW-3902 and that of [3H]-CHA. 4. KW-3902 showed potent A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively.

摘要

我们证明，通过放射性配体结合和细胞中环磷酸腺苷反应评估，8 -（降金刚烷-3-基）-1,3-二丙基黄嘌呤（KW-3902）是一种非常强效且选择性的腺苷A1受体拮抗剂。2. 在大鼠前脑用[3H]-环己基腺苷（CHA）标记的腺苷A1受体上，KW-3902的Ki值为0.19 nM，而在大鼠纹状体用[3H]-2-[对-（2-羧乙基）-苯乙氨基]-5'-N-乙基羧酰胺腺苷（CGS21680）标记的A2A受体上，其Ki值为170 nM，表明相对于A2A受体，A1受体选择性高890倍。10 microM的KW-3902对CHO细胞上表达的重组大鼠A3受体无影响。3. 用[3H]-KW-3902进行的饱和研究表明，它以高亲和力（Kd = 77 pM）和有限容量（Bmax = 470 fmol mg-1蛋白质）结合到单一类别的识别位点。在抑制[3H]-KW-3902结合的腺苷配体的药理学特征与[3H]-CHA的药理学特征之间观察到高度正相关。4. KW-3902对A1选择性激动剂环戊基腺苷抑制福斯高林诱导的DDT1 MF-2细胞中环磷酸腺苷积累表现出强效的A1拮抗作用，解离常数（KB值）为0.34 nM。KW-3902通过A2B受体拮抗5'-N-乙基羧酰胺腺苷引起的环磷酸腺苷积累，KB值为52 nM。5. KW-3902在结合亲和力上表现出明显的物种依赖性差异。对大鼠A1受体的亲和力最高（ki = 0.19 nM），豚鼠和犬A1受体的这些值分别为1.3和10 nM。