Article

Structure-based discovery of opioid analgesics with reduced side effects

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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.

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Acknowledgements

Supported by the US National Institutes of Health grants GM106990 (B.K.K., B.K.S. and P.G.), DA036246 (B.K.K.), GM59957 (B.K.S.), and the National Institutes of Mental Health Psychoactive Drug Screening Program (B.L.R.) and DA017204 (B.L.R., D.A.), DA035764 (B.L.R.) and the Michael Hooker Distinguished Professorship (B.L.R.) and the German Research Foundation Grants Gm 13/10 and GRK 1910 (P.G). A.M. received support from the Stanford University Medical Scientist Training Program (T32GM007365) and the American Heart Association (12PRE8120001).

Author information

Author notes

    • Aashish Manglik
    • , Henry Lin
    •  & Dipendra K. Aryal

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Aashish Manglik
    • , Grégory Scherrer
    •  & Brian K. Kobilka
  2. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA

    • Henry Lin
    • , Anat Levit
    • , Da Duan
    •  & Brian K. Shoichet
  3. Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA

    • Dipendra K. Aryal
    • , John D. McCorvy
    • , Xi-Ping Huang
    • , Maria F. Sassano
    • , Patrick M. Giguère
    •  & Bryan L. Roth
  4. Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany

    • Daniela Dengler
    • , Ralf C. Kling
    • , Viachaslau Bernat
    • , Harald Hübner
    • , Stefan Löber
    •  & Peter Gmeiner
  5. Department of Anesthesiology, Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine, Stanford, California 94305, USA

    • Gregory Corder
    •  & Grégory Scherrer
  6. Institut für Physiologie und Pathophysiologie, Paracelsus Medical University, 90419 Nuremberg, Germany

    • Ralf C. Kling

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Contributions

A.M. and H.L. initiated the project. H.L. performed docking and identified compounds to be tested in the initial and analogue screens. A.M. performed binding studies to identify initial hits and devised structure-guided optimization strategies for subsequent analogues. D.K.A. performed in vivo studies, including analgesia assays, mouse plethysmography, faecal boli accumulation studies, open field locomotor assay, and conditioned place preference. J.D.M., M.F.S. and P.M.G. performed radioligand binding and signalling studies. X.P.H. performed signalling studies and assessed compound activity against the GPCRome. D.De., V.B., S.L. and H.H. synthesized compounds and determined affinities by radioligand binding and performed signalling studies. A.L. and A.M. docked PZM21 and TRV130 and R.C.K. simulated PZM21 binding to μOR. G.C. performed reflexive and affective analgesia studies of μOR knockout mice and was supervised by G.S. D.Du. performed pharmacokinetic studies. The manuscript was written by A.M., H.L. and B.K.S. with editing and suggestions from B.L.R. and input from D.K.A., B.K.K. and P.G. P.G. supervised chemical synthesis of compounds and the separation and identification of diastereomers, B.K.K. supervised testing of initial docking hits, B.L.R. supervised radioligand binding, signalling and in vivo studies and B.K.S. supervised the compound discovery and design. The project was conceived by A.M., H.L., B.K.K., P.G., B.K.S and B.L.R.

Competing interests

A.M., H.L., P.G., D.D., B.K.K., B.L.R. and B.K.S. have filed a provisional patent on PZM21 and related molecules. A.M., P.G., B.K.K., B.L.R. and B.K.S. are consultants and co-founders of Epiodyne, a company seeking to develop novel analgesics.

Corresponding authors

Correspondence to Brian K. Kobilka or Peter Gmeiner or Bryan L. Roth or Brian K. Shoichet.

Reviewer Information Nature thanks G. Henderson, E. Kelly, B. Kieffer and J. Meiler for their contribution to the peer review of this work.

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