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Structure-based discovery of opioid analgesics with reduced side effects

Author

Listed:
  • Aashish Manglik

    (Stanford University School of Medicine)

  • Henry Lin

    (University of California)

  • Dipendra K. Aryal

    (UNC Chapel Hill Medical School)

  • John D. McCorvy

    (UNC Chapel Hill Medical School)

  • Daniela Dengler

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Gregory Corder

    (Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine)

  • Anat Levit

    (University of California)

  • Ralf C. Kling

    (Friedrich-Alexander-Universität Erlangen-Nürnberg
    Institut für Physiologie und Pathophysiologie, Paracelsus Medical University)

  • Viachaslau Bernat

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Harald Hübner

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Xi-Ping Huang

    (UNC Chapel Hill Medical School)

  • Maria F. Sassano

    (UNC Chapel Hill Medical School)

  • Patrick M. Giguère

    (UNC Chapel Hill Medical School)

  • Stefan Löber

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Da Duan

    (University of California)

  • Grégory Scherrer

    (Stanford University School of Medicine
    Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Peter Gmeiner

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Bryan L. Roth

    (UNC Chapel Hill Medical School)

  • Brian K. Shoichet

    (University of California)

Abstract

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

Suggested Citation

  • Aashish Manglik & Henry Lin & Dipendra K. Aryal & John D. McCorvy & Daniela Dengler & Gregory Corder & Anat Levit & Ralf C. Kling & Viachaslau Bernat & Harald Hübner & Xi-Ping Huang & Maria F. Sassano, 2016. "Structure-based discovery of opioid analgesics with reduced side effects," Nature, Nature, vol. 537(7619), pages 185-190, September.
    • Handle: RePEc:nat:nature:v:537:y:2016:i:7619:d:10.1038_nature19112
    DOI: 10.1038/nature19112
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    Cited by:

    1. Kouki Kawakami & Masataka Yanagawa & Suzune Hiratsuka & Misaki Yoshida & Yuki Ono & Michio Hiroshima & Masahiro Ueda & Junken Aoki & Yasushi Sako & Asuka Inoue, 2022. "Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Amal El Daibani & Joseph M. Paggi & Kuglae Kim & Yianni D. Laloudakis & Petr Popov & Sarah M. Bernhard & Brian E. Krumm & Reid H. J. Olsen & Jeffrey Diberto & F. Ivy Carroll & Vsevolod Katritch & Bern, 2023. "Molecular mechanism of biased signaling at the kappa opioid receptor," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Justine S. Paradis & Xiang Feng & Brigitte Murat & Robert E. Jefferson & Badr Sokrat & Martyna Szpakowska & Mireille Hogue & Nick D. Bergkamp & Franziska M. Heydenreich & Martine J. Smit & Andy Chevig, 2022. "Computationally designed GPCR quaternary structures bias signaling pathway activation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Björn D. M. Bean & Colleen J. Mulvihill & Riddhiman K. Garge & Daniel R. Boutz & Olivier Rousseau & Brendan M. Floyd & William Cheney & Elizabeth C. Gardner & Andrew D. Ellington & Edward M. Marcotte , 2022. "Functional expression of opioid receptors and other human GPCRs in yeast engineered to produce human sterols," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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