Journal article
Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia
CJ Draper-Joyce, R Bhola, J Wang, A Bhattarai, ATN Nguyen, I Cowie-Kent, K O’Sullivan, LY Chia, H Venugopal, C Valant, DM Thal, D Wootten, N Panel, J Carlsson, MJ Christie, PJ White, P Scammells, LT May, PM Sexton, R Danev Show all
Nature | Published : 2021
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 Gi..
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Awarded by National Institutes of Health
Funding Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia (NHMRC) project grants 1145420 and 1147291, NHMRC program grant 1050083, American Heart Association grant 17SDG33370094 and the National Institutes of Health grant R01GM132572. P.M.S., W.L.I. and D.W. are NHMRC Senior Principal Research, Career Development and Senior Research Fellows, respectively. C.J.D.-J., A.G. and D.M.T. are Australian Research Council Discovery Early Career Research Fellows. L.T.M. is an Australian Heart Foundation Future Leaders Fellow. J.C. acknowledges support from the Swedish Research Council (2017-04676). We are grateful to S. Charman and K. White for performing the VCP171 and MIPS521 plasma and liver microsome stability studies. We acknowledge use of facilities within the Monash Ramaciotti Cryo-EM platform. This work was supported by the MASSIVE HPC facility (https://www.massive.org.au) and the Extreme Science and Engineering Discovery Environment supercomputing award TG-MCB180049.