Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability.
Alexander M. Sherwood, Rachel Saylor Crowley, Kelly F Paton, Andrew Biggerstaff, Benjamin Neuenswander, Victor W Day, Bronwyn M Kivell, Thomas E Prisinzano
Journal of Medicinal Chemistry May 11, 2017 DOI: 10.1021/acs.jmedchem.7b00148 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | Spirobutyrolactone 14 Salvinorin A |
| Topics | Salvia divinorum |
| Key points | The authors report that replacing salvinorin A's A-ring acetate with a spirobutyrolactone yields compound 14, which retains similar κ-opioid potency and selectivity (EC50 = 0.6 ± 0.2 nM at κ; >10000 nM at μ and δ), is more metabolically resistant, and shows similar in vivo analgesic and anti-inflammatory effects. They describe this as the first such bioisosteric replacement producing a metabolically resistant derivative. |
Abstract
Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a κ-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0.6 ± 0.2 nM at κ; >10000 nM at μ and δ). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.
Comparable studies
Other theoretical and historical papers on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. | 2008 | Theoretical or philosophical paper | |
| The claustrum's proposed role in consciousness is supported by the effect and target localization of Salvia divinorum. | 2014 | Theoretical or philosophical paper | |
| Total Synthesis of (-)-Salvinorin A. | 2016 | Theoretical or philosophical paper | |
| Salvia Divinorum: entrSalvia divinorum: Entre la prohibición y la construcción de su conocimientoe a proibição e a construção do seu saber | 2022 | Theoretical or philosophical paper | |
| Salvia divinorum induces body awareness changes comparable to metamorphic symptoms in the Alice in Wonderland syndrome | 2019 | Theoretical or philosophical paper |
Citations in the library
Cited by 11
- Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents. Molecules October 11, 2018
- Total Synthesis of the Neoclerodane Diterpene Salvinorin A via an Intramolecular Diels–Alder Strategy Organic Letters May 22, 2018
- Cutting-Edge Search for Safer Opioid Pain Relief: Retrospective Review of Salvinorin A and Its Analogs. Frontiers in Psychiatry 2019
- The translational potential of salvinorin A: systematic review and meta-analysis of preclinical studies. Translational Psychiatry October 10, 2025
- Chemical syntheses of the salvinorin chemotype of KOR agonist. Natural Product Reports November 18, 2020
and 6 more in the library
Cites 18
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. Journal of Psychoactive Drugs 1994
- Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Psychopharmacology March 1, 2013
- Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug and Alcohol Dependence May 1, 2011
- Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Journal of Medicinal Chemistry December 26, 2014
and 13 more in the library