Barda David A, Wang Zhao-Qing, Britton Thomas C, Henry Steven S, Jagdmann G Erik, Coleman Darrell S, Johnson Michael P, Andis Sherri L, Schoepp Darryle D
Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Bioorg Med Chem Lett. 2004 Jun 21;14(12):3099-102. doi: 10.1016/j.bmcl.2004.04.017.
The major excitatory neurotransmitter in the Central Nervous System is L-glutamic acid. As a result much attention has been given to the discovery of selective modulators of both the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs). In this study we describe a novel class of subtype selective allosteric potentiators of the mGlu2 receptor. An active compound N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide, LY181837, was identified in the course of compound screening. The synthesis of two series of analogs examined the structural requirements of the diaryl region of this compound. This SAR study also resulted in compounds with an increase in potency of over 100-fold where the most potent compound reported has EC(50)=14 nM.
中枢神经系统中的主要兴奋性神经递质是L-谷氨酸。因此，离子型谷氨酸受体（iGluRs）和代谢型谷氨酸受体（mGluRs）的选择性调节剂的发现受到了广泛关注。在本研究中，我们描述了一类新型的mGlu2受体亚型选择性变构增强剂。在化合物筛选过程中鉴定出一种活性化合物N-(4-苯氧基苯基)-N-(3-吡啶基甲基)乙磺酰胺，LY181837。通过合成两个系列的类似物研究了该化合物二芳基区域的结构要求。该构效关系研究还得到了活性增强超过100倍的化合物，其中报道的最有效化合物的EC(50)=14 nM。
