2. Academic Validation
  3. Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

  • Nature. 2021 Sep;597(7877):571-576. doi: 10.1038/s41586-021-03897-2.
Christopher J Draper-Joyce 1 2,  Rebecca Bhola 3,  Jinan Wang 4,  Apurba Bhattarai 4,  Anh T N Nguyen 1,  India Cowie-Kent 3,  Kelly O'Sullivan 3,  Ling Yeong Chia 1,  Hariprasad Venugopal 5,  Celine Valant 1,  David M Thal 1,  Denise Wootten 1 6,  Nicolas Panel 7,  Jens Carlsson 7,  Macdonald J Christie 8,  Paul J White 1,  Peter Scammells 9,  Lauren T May 1,  Patrick M Sexton 1 6,  Radostin Danev 10,  Yinglong Miao 4,  Alisa Glukhova 11 12 13,  Wendy L Imlach 14,  Arthur Christopoulos 15 16
Affiliations

Affiliations

  • 1 Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 2 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
  • 3 Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
  • 4 Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
  • 6 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 7 Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
  • 8 Discipline of Pharmacology, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
  • 9 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 10 Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • 11 Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
  • 12 Structural Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [email protected].
  • 13 Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Victoria, Australia. [email protected].
  • 14 Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. [email protected].
  • 15 Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
  • 16 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
PMID: 34497422 DOI: 10.1038/s41586-021-03897-2
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.

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