Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics

Tal Weizmann; Abigail Pearce; Peter Griffin; Achille Schild; Maren Flaßhoff; Philipp Grossenbacher; Martin Lochner; Christopher A. Reynolds; Graham Ladds; Giuseppe Deganutti

doi:10.3390/cells13242121

Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics

Tal Weizmann, Abigail Pearce, Peter Griffin, Achille Schild, Maren Flaßhoff, Philipp Grossenbacher, Martin Lochner, Christopher A. Reynolds, Graham Ladds, Giuseppe Deganutti

Centre for Health and Life Sciences

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Abstract

The adenosine A1 receptor (A₁R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the positive allosteric modulator MIPS521 and the A1R-selective agonist BnOCPA, which are both potent and powerful analgesics with fewer side effects. While BnOCPA directly activates the A₁R from the canonical orthosteric site, MIPS521 binds to an allosteric site, acting in concert with orthosteric adenosine and tuning its pharmacology. Given their overlapping profile in pain models but distinct mechanisms of action, we combined pharmacology and microsecond molecular dynamics simulations to address MIPS521 and BnOCPA activity and their reciprocal influence when bound to the A1R. We show that MIPS521 changes adenosine and BnOCPA G protein selectivity in opposite ways and propose a structural model where TM7 dynamics are differently affected and involved in the G protein preferences of adenosine and BnOCPA.

Original language	English
Article number	2121
Number of pages	14
Journal	Cells
Volume	13
Issue number	24
DOIs	https://doi.org/10.3390/cells13242121
Publication status	Published - 21 Dec 2024

Bibliographical note

© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Funding

This research was funded by BBSCR, grant numbers BB/W016974/1 (C.A.R., G.D., T.W., and P.G.) and BB/W014831/1 (G.L. and A.P.). G.L. is also funded by a Royal Society Industry Fellowship (INF/R2/212001).

Funders	Funder number
Biotechnology and Biological Sciences Research Council	BB/W016974/1, BB/W014831/1
The Royal Society	INF/R2/212001

Keywords

adenosine A1 receptor
BnOCPA
GPCRs
MIPS521
non-opioid analgesia

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.3390/cells13242121Licence: CC BY

Deganutti2024VoRFinal published version, 2.35 MBLicence: CC BY

Cite this

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abstract = "The adenosine A1 receptor (A1R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the positive allosteric modulator MIPS521 and the A1R-selective agonist BnOCPA, which are both potent and powerful analgesics with fewer side effects. While BnOCPA directly activates the A1R from the canonical orthosteric site, MIPS521 binds to an allosteric site, acting in concert with orthosteric adenosine and tuning its pharmacology. Given their overlapping profile in pain models but distinct mechanisms of action, we combined pharmacology and microsecond molecular dynamics simulations to address MIPS521 and BnOCPA activity and their reciprocal influence when bound to the A1R. We show that MIPS521 changes adenosine and BnOCPA G protein selectivity in opposite ways and propose a structural model where TM7 dynamics are differently affected and involved in the G protein preferences of adenosine and BnOCPA.",

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Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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