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Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Author

Listed:
  • Christopher J. Draper-Joyce

    (Monash Institute of Pharmaceutical Sciences, Monash University
    University of Melbourne)

  • Rebecca Bhola

    (Monash University)

  • Jinan Wang

    (University of Kansas)

  • Apurba Bhattarai

    (University of Kansas)

  • Anh T. N. Nguyen

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • India Cowie-Kent

    (Monash University)

  • Kelly O’Sullivan

    (Monash University)

  • Ling Yeong Chia

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Hariprasad Venugopal

    (Monash University)

  • Celine Valant

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • David M. Thal

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Denise Wootten

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Monash University)

  • Nicolas Panel

    (Uppsala University)

  • Jens Carlsson

    (Uppsala University)

  • Macdonald J. Christie

    (University of Sydney)

  • Paul J. White

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Peter Scammells

    (Monash University)

  • Lauren T. May

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Patrick M. Sexton

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Monash University)

  • Radostin Danev

    (University of Tokyo)

  • Yinglong Miao

    (University of Kansas)

  • Alisa Glukhova

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Wendy L. Imlach

    (Monash University)

  • Arthur Christopoulos

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Monash University)

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.

Suggested Citation

  • 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., 2021. "Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia," Nature, Nature, vol. 597(7877), pages 571-576, September.
  • Handle: RePEc:nat:nature:v:597:y:2021:i:7877:d:10.1038_s41586-021-03897-2
    DOI: 10.1038/s41586-021-03897-2
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    Cited by:

    1. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Minfei Su & Navid Paknejad & Lan Zhu & Jinan Wang & Hung Nguyen Do & Yinglong Miao & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Shun Kaneko & Shunsuke Imai & Tomomi Uchikubo-Kamo & Tamao Hisano & Nobuaki Asao & Mikako Shirouzu & Ichio Shimada, 2024. "Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Zhihong Xiao & Jinyin Zha & Xu Yang & Tingting Huang & Shuxin Huang & Qi Liu & Xiaozheng Wang & Jie Zhong & Jianting Zheng & Rubing Liang & Zixin Deng & Jian Zhang & Shuangjun Lin & Shaobo Dai, 2024. "A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Hongmin Cai & Shimeng Guo & Youwei Xu & Jun Sun & Junrui Li & Zhikan Xia & Yi Jiang & Xin Xie & H. Eric Xu, 2024. "Cryo-EM structures of adenosine receptor A3AR bound to selective agonists," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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