Aashish Manglik 1 , Henry Lin 2 , Dipendra K Aryal 3 , John D McCorvy 3 , Daniela Dengler 4 , Gregory Corder 5 , Anat Levit 2 , Ralf C Kling 4 , 6 , Viachaslau Bernat 4 , Harald Hübner 4 , Xi-Ping Huang 3 , Maria F Sassano 3 , Patrick M Giguère 3 , Stefan Löber 4 , Da Duan 2 , Grégory Scherrer 1 , 5 , Brian K Kobilka 1 , Peter Gmeiner 4 , Bryan L Roth 3 , Brian K Shoichet 2
Sep 08 2016
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.