Structure–based discovery of opioid analgesics with reduced side effects

By A. Manglik, Henry Lin, Dipendra K. Aryal, J. McCorvy, D. Dengler, G. Corder, A. Levit, Ralf C. Kling, Viachaslau Bernat, H. Hübner and 10 more. Nature, 2016

863 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/366cb15d892f8209544b85dba992e35f0193bba6

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In Cellular and Molecular Neuroscience

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Citations in the corpus

Poorly controlled postoperative pain: prevalence, consequences, and prevention (2017, background): “PZM21, a selective μ-opioid-receptor agonist, has been shown potently to activate G-protein pathway signaling, with minimal β-arrestin 2 recruitment.(9) In preclinical studies, G-protein-mediated action of PZM21 on μ-receptor activity provided analgesia with an improved AE profile (eg, reduced const”
A practical guide to large-scale docking (2021, background): “Synthetic chemistry groups may obtain synthesis routes of the parent compound from the supplier allowing the generation of medicinal chemistry-inspired analog series 108 .”
Computational approaches streamlining drug discovery (2023, background): “Further steps in optimization of the initial hits obtained from standard screening libraries of less than 10 million compounds, however, usually require expensive custom synthesis of analogues, which has been afforded only in a few published cases 20,61 .”
Computational design of environmental sensors for the potent opioid fentanyl (2017, background): “Fentanyl is likely to make a direct salt bridge with MOR via its tertiary amine and a con- served aspartate in the third transmembrane helix of the receptor (Manglik et al., 2016; Manglik et al., 2012).”
5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology (2018, positive): “Structure-based drug design approaches have facilitated the creation of selective GPCR drugs (Wang et al., 2017) with improved therapeutic profiles, as exemplified by the recent discovery of m-opioid selective G protein-biased agonists (Manglik et al., 2016).”