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; Arthur Christopoulos

doi:10.1038/s41586-021-03897-2

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 DanevYinglong Miao, Alisa Glukhova, Wendy L. Imlach, Arthur Christopoulos

Research output: Contribution to journal › Article › Research › peer-review

96 Citations (Scopus)

Abstract

The adenosine A₁ receptor (A₁R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain^1,2. 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 G_i2 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.

Original language	English
Pages (from-to)	571–576
Number of pages	25
Journal	Nature
Volume	597
DOIs	https://doi.org/10.1038/s41586-021-03897-2
Publication status	Published - 23 Sept 2021

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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, 571–576. https://doi.org/10.1038/s41586-021-03897-2

@article{4b0f78099ad54318bb84a4209d7e2517,

title = "Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia",

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.",

author = "Draper-Joyce, {Christopher J.} and Rebecca Bhola and Jinan Wang and Apurba Bhattarai and Nguyen, {Anh T.N.} and India Cowie-Kent and Kelly O{\textquoteright}Sullivan and Chia, {Ling Yeong} and Hariprasad Venugopal and Celine Valant and Thal, {David M.} and Denise Wootten and Nicolas Panel and Jens Carlsson and Christie, {Macdonald J.} and White, {Paul J.} and Peter Scammells and May, {Lauren T.} and Sexton, {Patrick M.} and Radostin Danev and Yinglong Miao and Alisa Glukhova and Imlach, {Wendy L.} and Arthur Christopoulos",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

day = "23",

doi = "10.1038/s41586-021-03897-2",

language = "English",

volume = "597",

pages = "571–576",

journal = "Nature",

issn = "0028-0836",

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Draper-Joyce, CJ, Bhola, R, Wang, J, Bhattarai, A, Nguyen, ATN, Cowie-Kent, I, O’Sullivan, K, Chia, LY, Venugopal, H, Valant, C , Thal, DM , Wootten, D, Panel, N, Carlsson, J, Christie, MJ, White, PJ , Scammells, P , May, LT , Sexton, PM, Danev, R, Miao, Y, Glukhova, A, Imlach, WL & Christopoulos, A 2021, 'Positive allosteric mechanisms of adenosine A₁ receptor-mediated analgesia', Nature, vol. 597, pp. 571–576. https://doi.org/10.1038/s41586-021-03897-2

TY - JOUR

T1 - Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

AU - Draper-Joyce, Christopher J.

AU - Bhola, Rebecca

AU - Wang, Jinan

AU - Bhattarai, Apurba

AU - Nguyen, Anh T.N.

AU - Cowie-Kent, India

AU - O’Sullivan, Kelly

AU - Chia, Ling Yeong

AU - Venugopal, Hariprasad

AU - Valant, Celine

AU - Thal, David M.

AU - Wootten, Denise

AU - Panel, Nicolas

AU - Carlsson, Jens

AU - Christie, Macdonald J.

AU - White, Paul J.

AU - Scammells, Peter

AU - May, Lauren T.

AU - Sexton, Patrick M.

AU - Danev, Radostin

AU - Miao, Yinglong

AU - Glukhova, Alisa

AU - Imlach, Wendy L.

AU - Christopoulos, Arthur

N1 - Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/23

Y1 - 2021/9/23

N2 - 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.

AB - 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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U2 - 10.1038/s41586-021-03897-2

DO - 10.1038/s41586-021-03897-2

M3 - Article

AN - SCOPUS:85114651161

SN - 0028-0836

VL - 597

SP - 571

EP - 576

JO - Nature

JF - Nature

ER -

Positive allosteric mechanisms of adenosine A₁ receptor-mediated analgesia

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Adenosine A1 receptor modulation: Structure, dynamics & novel pharmacological interventions

Adenosine Receptor Context-Specific Biased Agonism to Treat Ischaemic Heart Disease

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Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

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Adenosine Receptor Context-Specific Biased Agonism to Treat Ischaemic Heart Disease

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Positive allosteric mechanisms of adenosine A₁ receptor-mediated analgesia