优化一系列醚类 mGlu5 正变构调节剂：MPEP 结合位点相互作用交叉的分子决定因素。
Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover.
机构信息
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2012 Oct 15;22(20):6481-5. doi: 10.1016/j.bmcl.2012.08.043. Epub 2012 Aug 24.
Abstract
We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
摘要
我们报告了一系列非 MPEP 位代谢型谷氨酸受体 5（mGlu(5)）正变构调节剂（PAMs）的优化，这些调节剂基于简单的无环醚系列。通过在烟酰胺核心中结合手性酰胺，修饰导致 MPEP 位相互作用的增加。一种高活性的 PAM，8v（VU0404251），在精神分裂症的啮齿动物模型中显示出疗效。这些研究表明，可以开发拓扑结构相似的化学型的有效 PAMs，以优先与 MPEP 变构结合位点相互作用或不相互作用。
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