Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ Opioid Receptor
Rachel S Crowley, Andrew P Riley, Amy F Alder, Richard J. Anderson, Dan Luo, Sophia Kaska, Pamela Maynez, Bronwyn M Kivell, Thomas E Prisinzano
ACS Chemical Neuroscience May 8, 2020 DOI: 10.1021/acschemneuro.0c00191 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Key findings | Compound 25 is a potent, G-protein-biased MOR agonist over 100 times more potent than morphine and over 5 times more potent than fentanyl in vitro, elicits antinociception with limited tolerance development in vivo, and lacks a basic nitrogen or ionizable groups. |
Abstract
Previous structure-activity relationship (SAR) studies identified the first centrally-acting, non-nitrogenous μ opioid receptor (MOR) agonist, kurkinorin (1), derived from salvinorin A. In an effort to further probe the physiological effects induced upon activation of MORs with this non-morphine scaffold, a variety of analogues were synthesized and evaluated in vitro for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased towards β-arrestin-2 recruitment or biased towards G-protein activation have been identified. One such compound, 25, has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively, 25 is over 100x more potent than morphine and over 5x more potent than fentanyl in vitro and elicits antinociception with limited tolerance development in vivo. This is especially significant given that 25 lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.
Comparable studies
Other experimental studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. | 2002 | Experimental study | |
| Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells and... | 2004 | Experimental study | |
| Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Animal model | 2014 | Experimental study | |
| Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. | 2005 | Experimental study | |
| Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Rat brain striatum homogenates | 2009 | Laboratory experiment |
Citations in the library
Cited by 3
- The translational potential of salvinorin A: systematic review and meta-analysis of preclinical studies. Translational Psychiatry October 10, 2025
- Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor Preprints.org November 1, 2022
- A Protecting-Group-Free Synthesis of (-)-Salvinorin A. Chemistry - A European Journal May 20, 2021
Cites 9
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- A Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT2A Receptor Journal of Medicinal Chemistry December 1, 1998
- Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A. Journal of Natural Products 2006
- Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor. European journal of medicinal chemistry October 6, 2014
- Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. British Journal of Pharmacology 2015
and 4 more in the library