Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of 2-Methyl-5-(1H-pyrazol-4-yl)pyridines and Related Heterocycles as Promising M4 mAChR Positive Allosteric Modulators for the Treatment of Neurocognitive Disorders
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-18 , DOI: 10.1021/acs.jmedchem.4c01207
Boqun Liu ₁ , Geoff Thompson ₂ , Manuela Jörg ₁ , Nicholas Barnes ₂ , David M Thal _{2,

3} , Arthur Christopoulos _{2,

3,

4} , Ben Capuano ₁ , Celine Valant _{2,

3} , Peter J Scammells ₁

Affiliation

The M₄ muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M₄ mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M₄ mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (G_oB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M₄ PAMs were assessed for their ability to modulate ACh-mediated β-arrestin recruitment and revealed 4 distinct clusters of M₄ PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward β-arrestin recruitment (23i). These novel M₄ chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and β-arrestin pathways in neurocognitive disorders.

中文翻译：

发现 2-甲基-5-(1H-吡唑-4-基)吡啶和相关杂环化合物作为有前景的 M4 mAChR 正变构调节剂用于治疗神经认知障碍

M ₄毒蕈碱乙酰胆碱受体 (mAChR) 是神经认知障碍的生物靶标。化合物1是 M ₄ mAChR 的ago -PAM。在此，我们报告了基于1 的新型假定 M ₄ mAChR PAM 的设计、合成和评估。这些类似物经过筛选，然后在两种功能测定（G _oB蛋白激活和 CAMYEL 激活）中进行全面表征，以量化它们针对 ACh 的变构和ago -PAM 特性。评估了选定的 7 个 M ₄ PAM 调节 ACh 介导的 β-抑制蛋白募集的能力，并揭示了 4 个不同的 M ₄ PAM 活性簇：(1) 与1 ( 24d ) 相似的类似物，(2) 仅表现出变构的类似物激动 ( 23d )，(3) CAMYEL 激活中变构特性增加的类似物 ( 23b / 23f和24a / 24b )，以及 (4) 对 β-抑制蛋白募集具有偏向调节作用的类似物 ( 23i )。这些新颖的 M ₄化学工具揭示了离散的分子决定因素，允许进一步探讨 cAMP 和 β-arrestin 通路在神经认知障碍中的治疗作用。

更新日期：2024-07-18

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南