Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia
No Preview Available
Citations
Scopus:
Altmetric:
Altmetric::
Associated Records
Authors
File Licence
Editors
Date
2021-09-23
Source Title
Nature
Journal Title
Journal ISSN
Volume Title
Publisher
NATURE PORTFOLIO
Melbourne Authors
Affiliation
Florey Department of Neuroscience and Mental Health
Biochemistry and Pharmacology
Biochemistry and Pharmacology
Document Type
Journal Article
Subject Code
Citation
Draper-Joyce, C. J., Bhola, R., Wang, J., Bhattarai, A., Nguyen, A. T. N., Cowie-Kent, I., O’Sullivan, K., Chia, L. Y., Venugopal, H., Valant, C., Thal, D. M., Wootten, D., Panel, N., Carlsson, J., Christie, M. J., White, P. J., Scammells, P., May, L. T., Sexton, P. M. ,... Christopoulos, A. (2021). Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia. Nature, 597 (7877), pp.571-576. https://doi.org/10.1038/s41586-021-03897-2.
Access Status
Access this item via the Open Access location
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
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.