The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries.
The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries.
复制标题
从组合文库中分离出的新型MCH1受体拮抗剂的药理特性。
DOI：
10.1016/j.ejphar.2008.10.068
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发表时间：
2009-01-14
影响因子：
5
通讯作者：
Civelli O
中科院分区：
文献类型：
--
作者：
Nagasaki H;Chung S;Dooley CT;Wang Z;Li C;Saito Y;Clark SD;Houghten RA;Civelli O
黑色素浓缩激素（MCH）是一种神经肽，表现出强大的促氧活性。在啮齿动物中，它通过与中枢神经系统（CNS）许多部位表达的一种受体MCH1受体相互作用来发挥作用。为了研究MCH系统的生理意义，我们需要能够局部和急性阻断它。这就需要使用MCH1受体拮抗剂。虽然MCH1受体拮抗剂以前已经报道过，但它们主要无法用于学术研究。我们在此采用一种策略，分离出高亲和力和选择性的MCH1受体拮抗剂，无需进一步的化学修饰即可进行体内分析。该拮抗剂TPI 1361-17是在只允许鉴定高亲和力化合物的条件下，通过筛选多个非肽位置扫描合成组合文库（PS-SCL）鉴定出的，总计超过80万种化合物。TPI 1361-17抑制MCH诱导的1 nM Ca2+动员的IC50值为6.1 nM，并完全取代[125I] MCH与大鼠MCH1受体的结合。发现TPI 1361-17具有特异性，对多种其他g蛋白偶联受体和通道没有亲和力。TPI 1361-17在体内具有活性，可阻断mch诱导的食物摄入75%。结果表明，TPI 1361-17是一种新型的选择性MCH1受体拮抗剂，是研究MCH系统生理功能的有效工具。这些结果也说明了组合文库筛选在学术环境中识别特定替代拮抗剂的成功应用。
Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits potent orexigenic activity. In rodents, it exerts its actions by interacting with one receptor, MCH1 receptor which is expressed in many parts of the central nervous system (CNS). To study the physiological implications of the MCH system, we need to be able to block it locally and acutely. This necessitates the use of MCH1 receptor antagonists. While MCH1 receptor antagonists have been previously reported, they are mainly not accessible to academic research. We apply here a strategy that leads to the isolation of a high affinity and selective MCH1 receptor antagonist amenable to in vivo analyses without further chemical modifications. This antagonist, TPI 1361-17, was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight hundred thousand compounds in conditions that allow for the identification of only high-affinity compounds. TPI 1361-17 exhibited an IC50 value of 6.1 nM for inhibition of 1 nM MCH-induced Ca2+ mobilization and completely displaced the binding of [125I] MCH to rat MCH1 receptor. TPI 1361-17 was found specific, having no affinity for a variety of other G-protein coupled receptors and channels. TPI 1361-17 was found active in vivo since it blocked MCH-induced food intake by 75 %. Our results indicate that TPI 1361-17 is a novel and selective MCH1 receptor antagonist and is an effective tool to study the physiological functions of the MCH system. These results also illustrate the successful application of combinatorial library screening to identify specific surrogate antagonists in an academic setting.
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影响因子：
3.2
作者：
Kennedy, AR;Todd, JF;Bloom, SR
通讯作者：
Bloom, SR
影响因子：
7.3
作者：
Handlon, Anthony L.;Zhou, Huiqiang
通讯作者：
Zhou, Huiqiang
影响因子：
82.9
作者：
Pinilla, Clemencia;Appel, Jon R.;Houghten, Richard A.
通讯作者：
Houghten, Richard A.
影响因子：
7.7
作者：
Bradley, RL;Kokkotou, EG;Cheatham, B
通讯作者：
Cheatham, B
影响因子：
3.6
作者：
Macdonald, D;Murgolo, N;Graziano, MP
通讯作者：
Graziano, MP