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Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112. Epub 2016 Aug 17.

Structure-based discovery of opioid analgesics with reduced side effects.

Author information

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.

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.

PMID:
27533032
PMCID:
PMC5161585
DOI:
10.1038/nature19112
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare competing financial interests: details are available in the online version of the paper. Readers are welcome to comment on the online version of the paper.

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