Structure-based discovery of opioid analgesics with reduced side effects

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.

Strategy for making safer opioids bolstered

“…A few promising drug candidates have been identified that might help to answer this question -for example, in mice, the preclinical candidates PZM21 (ref. 17) and mitragynine pseudoindoxyl 19 exhibit some G-protein bias and clearly separate µOR-mediated analgesia from adverse side effects, including respiratory depression, constipation and capacity for abuse. However, a study in rodents indicates that TRV130 retains the potential for abuse 20 .…”

“…These findings support the idea 14 that opioid agonists with a strong bias towards G-protein-mediated signalling will retain their analgesic properties, but produce fewer side effects than unbiased opioids. Several laboratories have since identified G-protein-biased µOR agonists 4,[15][16][17][18][19] , many of which clearly separate analgesia from adverse side effects. One of these compounds, known as TRV130, is currently in phase III clinical trials 16 .…”

Therapies and Mechanisms of Opioid Withdrawal

“…Activation of downstream inhibitory G-proteins coupled to opioid receptors recruits the β-arrestin signalling pathway, which subsequently contributes to the unwanted side-effects of opioid treatment [18]. Using computational screening and structure-based engineering, a new ligand known as PMZ21 was developed, with a powerful ability to activate inhibitory G-proteins with minimal β-arrestin recruitment [19]. Another approach involved refining the site of opioid action, specifically within the pain pathways.…”

The drug-maker's guide to the galaxy

“…The team screened more than 3 million commercially available compounds to find candidates that would selectively activate μ-opioid receptor signalling to relieve pain without disturbing the closely related β-arrestin signalling pathway -which is thought to be associated with opioid side effects including a lowered breathing rate and constipation. The researchers quickly whittled down a massive compound library to just 23 highly ranked compounds for follow-up 2 .…”