代谢型谷氨酸受体 2 沉默变构调节剂的化学开关转化为双重代谢型谷氨酸受体 2/3 负/正变构调节剂。

Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators.

机构信息

Domain Therapeutics SA, Bioparc, Boulevard Sebastien Brant, F-67400 Strasbourg-Illkirch, France. sschann@domaintherapeutics

出版信息

J Med Chem. 2010 Dec 23;53(24):8775-9. doi: 10.1021/jm101069m. Epub 2010 Nov 24.

DOI:10.1021/jm101069m

PMID:21105727

Abstract

Using an mGluR2 FRET-based binding assay, binders of the transmembrane region devoid of functional activity were identified. It is reported that slight chemical modifications of these SAMs can dramatically change activity of the resulting analogues without altering their affinities. Starting from compound 1, three mGluR2 NAMs showing also mGluR3 PAM activities were obtained. SAMs therefore represent a useful approach to explore the chemical space for GPCR allosteric modulator identification.

摘要

利用基于 mGluR2 FRET 的结合测定法，鉴定出了缺乏功能活性的跨膜区域结合物。据报道，这些 SAM 的轻微化学修饰可以在不改变其亲和力的情况下，显著改变所得类似物的活性。从化合物 1 开始，获得了三种也显示 mGluR3 PAM 活性的 mGluR2 NAMs。因此，SAM 代表了一种用于探索 GPCR 变构调节剂鉴定的化学空间的有用方法。