变构调节
变构调节剂
腺苷
药理学
化学
腺苷受体
神经病理性疼痛
受体
止痛药
跨膜结构域
配体(生物化学)
兴奋剂
医学
生物化学
作者
Christopher J. Draper-Joyce,Rebecca F. Bhola,Jinan Wang,Apurba Bhattarai,Thi Nguyen,India Cowie-Kent,Kelly O’Sullivan,Ling Yeong Chia,Hariprasad Venugopal,Céline Valant,David M. Thal,Denise Wootten,Nicolas Panel,Jens Carlsson,MacDonald J. Christie,Paul J. White,Peter J. Scammells,Lauren T. May,Patrick M. Sexton,Radostin Danev
出处
期刊:Nature
[Springer Nature]
日期:2021-09-08
卷期号:597 (7877): 571-576
被引量:148
标识
DOI:10.1038/s41586-021-03897-2
摘要
The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. 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 A1R, 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 A1R co-bound to adenosine, MIPS521 and a Gi2 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.
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