Abstract：
Metabotropic glutamate (Glu) receptors (mGlu receptors) play a key role in modulating excitatory neurotransmission in the central nervous system (CNS). In this study, we report the structure-based design and pharmacological evaluation of densely functionalized, conformationally restricted glutamate analogue (1S,2S,3S)-2-((S)-amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic acid (LBG30300). LBG30300 was synthesized in a stereocontrolled fashion in nine steps from a commercially available optically active epoxide. Functional characterization of all eight mGlu receptor subtypes showed that LBG30300 is a picomolar agonist at mGlu2 with excellent selectivity over mGlu3 and the other six mGlu receptor subtypes. Bioavailability studies on mice (IV administration) confirm CNS exposure, and an in silico study predicts a binding mode of LBG30300 which induces a flipping of Tyr144 to allow for a salt bridge interaction of the acetate group with Arg271. The Tyr144 residue now prevents Arg271 from interacting with Asp146, which is a residue of differentiation between mGlu2 and mGlu3 and thus could explain the observed subtype selectivity.
摘要：
代谢型谷氨酸（Glu）受体（mGlu受体）在调节中枢神经系统（CNS）的兴奋性神经传递中起关键作用。在这项研究中,我们报告了密集功能化的基于结构的设计和药理学评估，构象受限的谷氨酸类似物(1S，2S,3S)-2-((S)-氨基(羧基)甲基)-3-(羧基甲基)环丙烷-1-羧酸(LBG30300)。LBG30300以立体控制的方式在九个步骤中由市售的光学活性环氧化物合成。所有八种mGlu受体亚型的功能表征表明，LBG30300是mGlu2的皮摩尔激动剂，对mGlu3和其他六种mGlu受体亚型具有出色的选择性。小鼠的生物利用度研究（IV给药）证实中枢神经系统暴露，并且一项计算机模拟研究预测了LBG30300的结合模式，该模式引起Tyr144的翻转，以允许乙酸基团与Arg271的盐桥相互作用。Tyr144残基现在阻止Arg271与Asp146相互作用，Asp146是mGlu2和mGlu3之间的区别残基，因此可以解释观察到的亚型选择性。
