Structure-based discovery of opioid analgesics with reduced side effects

Aashish Manglik, Henry Lin, Dipendra K. Aryal, John D. McCorvy, Daniela Dengler, Gregory Corder, Anat Levit, Ralf C. Kling, Viachaslau Bernat, Harald Hübner, Xi-Ping Huang, Maria F. Sassano, Patrick M. Giguère, Stefan Löber, Da Duan, Grégory Scherrer, Brian K. Kobilka (), Peter Gmeiner (), Bryan L. Roth () and Brian K. Shoichet ()
Additional contact information
Aashish Manglik: Stanford University School of Medicine
Henry Lin: University of California
Dipendra K. Aryal: UNC Chapel Hill Medical School
John D. McCorvy: UNC Chapel Hill Medical School
Daniela Dengler: Friedrich-Alexander-Universität Erlangen-Nürnberg
Gregory Corder: Perioperative and Pain Medicine, Neurosurgery, Stanford Neurosciences Institute, Stanford University School of Medicine
Anat Levit: University of California
Ralf C. Kling: Friedrich-Alexander-Universität Erlangen-Nürnberg
Viachaslau Bernat: Friedrich-Alexander-Universität Erlangen-Nürnberg
Harald Hübner: Friedrich-Alexander-Universität Erlangen-Nürnberg
Xi-Ping Huang: UNC Chapel Hill Medical School
Maria F. Sassano: UNC Chapel Hill Medical School
Patrick M. Giguère: UNC Chapel Hill Medical School
Stefan Löber: Friedrich-Alexander-Universität Erlangen-Nürnberg
Da Duan: University of California
Grégory Scherrer: Stanford University School of Medicine
Brian K. Kobilka: Stanford University School of Medicine
Peter Gmeiner: Friedrich-Alexander-Universität Erlangen-Nürnberg
Bryan L. Roth: UNC Chapel Hill Medical School
Brian K. Shoichet: University of California

Nature, 2016, vol. 537, issue 7619, 185-190

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19112

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