Structure-based discovery of opioid analgesics with reduced side effects

Manglik A, Lin H, Aryal DK, Mccorvy JD, Dengler D, Corder G, Levit A, Kling R, Bernat V, Hübner H, Huang XP, Sassano MF, Giguere PM, Löber S, Duan D, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK (2016)

Publication Language: English

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2016

Journal

Publisher: Nature Publishing Group

Book Volume: 537

Pages Range: 185-190

Journal Issue: 7619

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 mu-opioid-receptor (mu OR) signalling through the beta-arrestin pathway or by actions at other receptors. Conversely, G-protein mu OR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the mu OR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent G(i) activator with exceptional selectivity for mu OR and minimal beta-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 mu OR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

Stanford University United States (USA) (US) University of North Carolina at Chapel Hill United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US)

How to cite

APA:

Manglik, A., Lin, H., Aryal, D.K., Mccorvy, J.D., Dengler, D., Corder, G.,... Shoichet, B.K. (2016). Structure-based discovery of opioid analgesics with reduced side effects. Nature, 537(7619), 185-190. https://doi.org/10.1038/nature19112

MLA:

Manglik, Aashish, et al. "Structure-based discovery of opioid analgesics with reduced side effects." Nature 537.7619 (2016): 185-190.

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