Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

Filippo Erli,Mariana Spetea,Birgit Waltenberger,Daniela Schuster,Teresa Kaserer,Roman Kainhofer,Sonja Sturm,Theresa Steinacher

doi:10.1038/s41598-020-70493-1

Filippo Erli, Mariana Spetea + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-70493-1

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Abstract

Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. Amongst the neurotransmitter systems involved in pain perception and modulation, the mu-opioid receptor (MOR), a G protein-coupled receptor, represents one of the most important targets for achieving effective pain relief. Most clinically used opioid analgesics are agonists to the MOR, but they can also cause severe side effects. Medicinal plants represent important sources of new drug candidates, with morphine and its semisynthetic analogues as well-known examples as analgesic drugs. In this study, combining in silico (pharmacophore-based virtual screening and docking) and pharmacological (in vitro binding and functional assays, and behavioral tests) approaches, we report on the discovery of two naturally occurring plant alkaloids, corydine and corydaline, as new MOR agonists that produce antinociceptive effects in mice after subcutaneous administration via a MOR-dependent mechanism. Furthermore, corydine and corydaline were identified as G protein-biased agonists to the MOR without inducing β-arrestin2 recruitment upon receptor activation. Thus, these new scaffolds represent valuable starting points for future chemical optimization towards the development of novel opioid analgesics, which may exhibit improved therapeutic profiles.

Highlights

Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis
By combining molecular modeling and pharmacological approaches, we report on the discovery of two plant-derived alkaloids, corydine [1] and corydaline [2] (Fig. 2), as new mu-opioid receptor (MOR) agonists with a G protein-biased profile
As none of the molecules matched any of the models when mapping of all features was required, the number of omitted features was increased to one, which means that compounds are recognized as potentially active compounds if they miss one of the model features

Summary

Introduction

Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. By combining molecular modeling and pharmacological approaches, we report on the discovery of two plant-derived alkaloids, corydine [1] and corydaline [2] (Fig. 2), as new MOR agonists with a G protein-biased profile.

Results

Conclusion