2. Academic Validation
  3. Structure-based discovery of opioid analgesics with reduced side effects

Structure-based discovery of opioid analgesics with reduced side effects

  • Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112.
Aashish Manglik 1,  Henry Lin 2,  Dipendra K Aryal 3,  John D McCorvy 3,  Daniela Dengler 4,  Gregory Corder 5,  Anat Levit 2,  Ralf C Kling 4 6,  Viachaslau Bernat 4,  Harald Hübner 4,  Xi-Ping Huang 3,  Maria F Sassano 3,  Patrick M Giguère 3,  Stefan Löber 4,  Da Duan 2,  Grégory Scherrer 1 5,  Brian K Kobilka 1,  Peter Gmeiner 4,  Bryan L Roth 3,  Brian K Shoichet 2
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
  • 2 Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
  • 3 Department of Pharmacology, UNC Chapel Hill Medical School, Chapel Hill, North Carolina 27514, USA.
  • 4 Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
  • 5 Department of Anesthesiology, Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
  • 6 Institut für Physiologie und Pathophysiologie, Paracelsus Medical University, 90419 Nuremberg, Germany.
PMID: 27533032 DOI: 10.1038/nature19112
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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