Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
Nature. 2021 Sep;597(7877):571-576. doi: 10.1038/s41586-021-03897-2. Epub 2021 Sep 8.
The adenosine A receptor (AR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain. However, development of analgesic orthosteric AR agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the AR, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the AR co-bound to adenosine, MIPS521 and a G heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.
腺苷 A 受体 (AR) 是一种有前途的治疗靶点，可用于开发非阿片类镇痛剂来治疗神经性疼痛。然而，由于缺乏足够的靶标选择性和组织外不良反应，镇痛性 AR 正构激动剂的开发已经失败。在这里，我们展示了 [2-氨基-4-(3,5-双（三氟甲基）苯基)噻吩-3-基)(4-氯苯基)甲酮]（MIPS521），一种 AR 的正变构调节剂，通过调节神经病理性疼痛大鼠脊髓中内源性腺苷水平的升高，在体内表现出镇痛功效。我们还报告了 AR 与腺苷、MIPS521 和 G 异三聚体共结合的结构，揭示了一个位于跨膜螺旋 1、6 和 7 之外的、面向脂双层的变构结合口袋。分子动力学模拟和配体动力学结合实验支持了一种机制，即 MIPS521 稳定了腺苷受体-G 蛋白复合物。这项研究为基于结构的非阿片类镇痛剂的变构药物设计提供了概念验证，这种药物针对特定的疾病背景。
