Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist,Journal of Medicinal Chemistry

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Design, Synthesis, Pharmacology, and In Silico Studies of (1S,2S,3S)-2-((S)-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu2 Receptor Agonist
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-03 , DOI: 10.1021/acs.jmedchem.3c01811
Na Liu ₁ , Floriane Eshak ₂ , Fanny Malhaire ₃ , Isabelle Brabet ₃ , Laurent Prézeau ₃ , Emma Renard ₁ , Jean-Philippe Pin ₃ , Francine C Acher ₂ , Markus Staudt ₁ , Lennart Bunch ₁

Affiliation

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.

中文翻译：

(1S,2S,3S)-2-((S)-氨基(羧基)甲基)-3-(羧甲基)环丙烷-1-甲酸 (LBG30300) 的设计、合成、药理学和计算机研究：皮摩尔效力亚型选择性 mGlu2 受体激动剂

代谢型谷氨酸 (Glu) 受体（mGlu 受体）在调节中枢神经系统 (CNS) 兴奋性神经传递中发挥关键作用。在本研究中，我们报告了密集功能化、构象限制的谷氨酸类似物 (1 S ,2 S ,3 S )-2-(( S )-氨基(羧基)甲基)-3-(羧甲基）环丙烷-1-甲酸（ LBG30300 ）。 LBG30300是由市售光学活性环氧化物以立体控制方式通过九个步骤合成的。所有八种 mGlu 受体亚型的功能表征表明， LBG30300是 mGlu ₂的皮摩尔激动剂，与 mGlu ₃和其他六种 mGlu 受体亚型相比具有优异的选择性。对小鼠的生物利用度研究（IV 给药）证实了 CNS 暴露，并且计算机模拟研究预测了LBG30300的结合模式，该模式会诱导 Tyr144 翻转，从而允许乙酸基团与 Arg271 发生盐桥相互作用。 Tyr144 残基现在阻止 Arg271 与 Asp146 相互作用，Asp146 是 mGlu ₂和 mGlu ₃之间的分化残基，因此可以解释观察到的亚型选择性。

更新日期：2024-01-03

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