Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016 Sep 08;537(7619):185-190
Date
08/18/2016Pubmed ID
27533032Pubmed Central ID
PMC5161585DOI
10.1038/nature19112Scopus ID
2-s2.0-84984612101 (requires institutional sign-in at Scopus site) 686 CitationsAbstract
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.
Author List
Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hübner H, Huang XP, Sassano MF, Giguère PM, Löber S, Da Duan, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BKAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnalgesiaAnalgesics, Opioid
Animals
Drug Discovery
GTP-Binding Protein alpha Subunits, Gi-Go
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Docking Simulation
Pain
Receptors, Opioid, mu
Spiro Compounds
Structure-Activity Relationship
Thiophenes
Urea
