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      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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          Author and article information

          Journal
          Nature
          Nature
          Springer Nature
          1476-4687
          0028-0836
          Sep 08 2016
          : 537
          : 7619
          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.
          Article
          nature19112 NIHMS825116
          10.1038/nature19112
          5161585
          27533032

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