Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Christopher J. Draper-Joyce, Rebecca Bhola, Jinan Wang, Apurba Bhattarai, Anh T. N. Nguyen, India Cowie-Kent, Kelly O’Sullivan, Ling Yeong Chia, Hariprasad Venugopal, Celine Valant, David M. Thal, Denise Wootten, Nicolas Panel, Jens Carlsson, Macdonald J. Christie, Paul J. White, Peter Scammells, Lauren T. May, Patrick M. Sexton, Radostin Danev, Yinglong Miao, Alisa Glukhova (), Wendy L. Imlach () and Arthur Christopoulos ()
Additional contact information
Christopher J. Draper-Joyce: Monash Institute of Pharmaceutical Sciences, Monash University
Rebecca Bhola: Monash University
Jinan Wang: University of Kansas
Apurba Bhattarai: University of Kansas
Anh T. N. Nguyen: Monash Institute of Pharmaceutical Sciences, Monash University
India Cowie-Kent: Monash University
Kelly O’Sullivan: Monash University
Ling Yeong Chia: Monash Institute of Pharmaceutical Sciences, Monash University
Hariprasad Venugopal: Monash University
Celine Valant: Monash Institute of Pharmaceutical Sciences, Monash University
David M. Thal: Monash Institute of Pharmaceutical Sciences, Monash University
Denise Wootten: Monash Institute of Pharmaceutical Sciences, Monash University
Nicolas Panel: Uppsala University
Jens Carlsson: Uppsala University
Macdonald J. Christie: University of Sydney
Paul J. White: Monash Institute of Pharmaceutical Sciences, Monash University
Peter Scammells: Monash University
Lauren T. May: Monash Institute of Pharmaceutical Sciences, Monash University
Patrick M. Sexton: Monash Institute of Pharmaceutical Sciences, Monash University
Radostin Danev: University of Tokyo
Yinglong Miao: University of Kansas
Alisa Glukhova: Monash Institute of Pharmaceutical Sciences, Monash University
Wendy L. Imlach: Monash University
Arthur Christopoulos: Monash Institute of Pharmaceutical Sciences, Monash University

Nature, 2021, vol. 597, issue 7877, 571-576

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03897-2

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