Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor
Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor
复制标题
DOI：
10.1074/jbc.273.25.15687
复制
发表时间：
1998-06-19
影响因子：
4.8
通讯作者：
Horuk, R
中科院分区：
文献类型：
--
作者：
Hesselgesser, J;Ng, HP;Horuk, R
CC趋化因子巨噬细胞炎性蛋白-1 α（MIP-1 α）和RANTES（regulated on activation normal T cell expressed）在类风湿关节炎和多发性硬化中起重要作用，由于它们的作用是通过CCR 1趋化因子受体介导的，因此我们建立了一个小分子CCR 1拮抗剂项目来寻找抑制剂。通过高容量筛选，我们发现了一些具有CCR 1拮抗活性的4-羟基哌啶化合物，并报道了它们的合成和体外药理学。竞争结合数据的Scatchard分析显示，化合物的Ki值范围为40至4000 nM。进一步评价了该系列中最有效的成员化合物1（2-2-二苯基-5-（4-氯苯基）哌啶-1-基）戊腈）的药理学特征。化合物1显示对MIP-1 α诱导的细胞外酸化和Ca 2+动员的浓度依赖性抑制，表明功能性拮抗作用。当单独给药时，该化合物未引起任何反应，表明不存在内在激动剂活性。化合物1以剂量响应方式抑制MIP-1 α和RANTES诱导的外周血单核细胞迁移。对一组7个跨膜结构域受体的选择性测试表明，化合物1在浓度高达10 μ M时对许多受体无活性。这是第一次描述的CCR 1受体拮抗剂，可能是有用的治疗慢性炎症性疾病，涉及MIP-1 α，RANTES，和CCR 1。
The CC chemokines macrophage inflammatory pro tein-1 alpha (MIP-1 alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis, Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had K-i values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitrite), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1 alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1 alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 mu M. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1 alpha, RANTES, and CCR1.