Discovery of Novel, Selective, and Nonbasic Agonists for the Kappa-Opioid Receptor Determined by Salvinorin A-Based Virtual Screening.
Kristina Puls, Aina-Leonor Olivé-Marti, Siriwat Hongnak, David Lamp, Mariana Spetea, Gerhard Wolber
Journal of Medicinal Chemistry August 22, 2024 DOI: 10.1021/acs.jmedchem.4c00590 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical in vitro study using structure-based virtual screening Peer reviewed |
|---|---|
| Interventions | SalA-VS-07 SalA-VS-08 |
| Topics | Salvia divinorum |
| Key points | Structure-based virtual screening using 3D pharmacophore models based on Salvinorin A's binding mode identified two nonbasic compounds, SalA-VS-07 and SalA-VS-08, which in vitro studies confirmed as highly selective KOR agonists with G protein-biased activity. Both share a novel spiro-moiety and nonbasic scaffold, and the authors propose them as starting points for therapeutics targeting KOR-related conditions such as pain. |
Abstract
Modulating the kappa-opioid receptor (KOR) is a promising strategy for treating various human diseases. KOR agonists show potential for treating pain, pruritus, and epilepsy, while KOR antagonists show potential for treating depression, anxiety, and addiction. The diterpenoid Salvinorin A (SalA), a secondary metabolite of Salvia divinorum, is a potent and selective KOR agonist. Unlike typical opioids, SalA lacks a basic nitrogen, which encouraged us to search for nonbasic KOR ligands. Through structure-based virtual screening using 3D pharmacophore models based on the binding mode of SalA, we identified novel, nonbasic, potent, and selective KOR agonists. In vitro studies confirmed two virtual hits, SalA-VS-07 and SalA-VS-08, as highly selective for the KOR and showing G protein-biased KOR agonist activity. Both KOR ligands share a novel spiro-moiety and a nonbasic scaffold. Our findings provide novel starting points for developing therapeutics aimed at treating pain and other conditions in which KOR is a central player.
Citations in the library
Cites 16
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin A: from natural product to human therapeutics. Molecular interventions October 1, 2006
- Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. Biochemistry June 21, 2005
- Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor. Biochemistry July 28, 2009
- Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects Pharmaceuticals February 3, 2021
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