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

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Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hubner H, Huang XP, Sassano MF, Giguere PM, Lober S, Da Duan, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK

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

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

PubMed ID

27533032 [ View in PubMed

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

DrugBank Data that Cites this Article

Drugs

Oliceridine

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Oliceridine	Mu-type opioid receptor	Protein	Humans	Yes	Agonist	Details