Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the beta-turn.
Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the beta-turn.
复制标题
通过筛选基于 β 转角的小分子库，鉴定出激活小鼠黑皮质素-1 受体的化合物。
DOI：
10.1021/jm990190s
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发表时间：
1999
影响因子：
7.3
通讯作者：
Cone,RD
中科院分区：
文献类型：
--
作者：
Haskell-Luevano,C;Rosenquist,A;Souers,A;Khong,KC;Ellman,JA;Cone,RD
对基于β-Turn基序的951种化合物的库进行了测试，以了解它们刺激黑素皮质素-1受体的能力。从这个筛选过程中，我们已经鉴定出两个在mMC1R具有低微摩尔激动剂活性的化合物。化合物EL1在i+1位，dPro在i+2位，Trp在i+3位，其EC50值为42.5±6.9μM。化合物EL2与Trp在i+1位，dLys在i+2位，Phe在i+3位，EC50值为63.4±26.9μM。文库筛选过程的结果与20世纪80年代提出的一个假说一致，即涉及黑色素皮质素“Phe-Arg-Trp”核心氨基酸的β-Turn构象提供了关键识别元件。此外，这些化合物是迄今为止报道的第一个能够激活MC1R的非肽杂环分子，MC1R是一种参与皮肤色素沉着和动物皮毛着色的黑素细胞受体。
A library of 951 compounds based upon the β-turn motif were examined for their ability to stimulate the melanocortin-1 receptor. From this screening process, we have identified two compounds possessing low micromolar agonist activity at the mMC1R. The compoundEL1with racemic Nal(2‘) in thei+ 1 position,dPro in thei+ 2 position, and Trp in thei+ 3 position possesses an EC50of 42.5 ± 6.9 μM. CompoundEL2with Trp in thei+ 1 position,dLys in thei+ 2 position, and Phe in thei+ 3 position possesses an EC50value of 63.4 ± 26.9 μM. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a β-turn conformation involving the melanocortin “Phe-Arg-Trp” core amino acids provides the key recognition element. Additionally, these compounds represent the first nonpeptidic heterocyclic molecules reported to date that are able to activate the MC1R, a melanocyte receptor involved in skin pigmentation and animal coat coloration.