Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues.
Cécile Béguin, Justin Potuzak, Wei Xu, Lee-Yuan Liu-Chen, John M Streicher, Chad E Groer, Laura M Bohn, William A Carlezon, Bruce M Cohen
Bioorganic & Medicinal Chemistry Letters January 15, 2012 DOI: 10.1016/j.bmcl.2011.11.128 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical laboratory study Peer reviewed |
|---|---|
| Interventions | 12-epi-salvinorin A salvinorin analogues nalbuphine |
| Measures | DiscoveRx beta-arrestin2 assay, G protein activation assay |
| Topics | Salvia divinorum |
| Key points | 12-epi-salvinorin A partially activated G protein signaling at the kappa opioid receptor but acted as a full agonist in the beta-arrestin2 DiscoveRx assay, while the other salvinorin analogues tested were full agonists in both assays. Nalbuphine was a partial agonist in both pathways. |
Abstract
The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five analogues of 12-epi-salvinorin A were synthesized and their effects on G protein activation as well as β-arrestin2 recruitment were evaluated. Only 12-epi-salvinorin A (1) partially activated signaling through G proteins, yet acted as a full agonist in the β-arrestin 2 DiscoveRx assay. Other salvinorin analogues tested in these functional assays were full agonists in both assays of KOPR activation. By comparison, the non-selective opioid ligand nalbuphine, known to be a partial agonist for G-protein activation, was also a partial agonist for the β-arrestin mediated signaling pathway activated through KOPR.
Comparable studies
Other preclinical and animal studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Mice | 2005 | Experimental study | |
| Potential anxiolytic‐ and antidepressant‐like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents Male Sprague-Dawley rats and male Albino Swiss mice | 2009 | Experimental study | |
| Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward. Wistar rats | 2008 | Experimental study | |
| Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Rats | 2010 | Experimental study | |
| The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Rhesus monkeys | 2004 | Experimental study | n = 3 |
Citations in the library
Cited by 7
- Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders Frontiers in Pharmacology September 8, 2015
- Semisynthetic neoclerodanes as kappa opioid receptor probes. Bioorganic & Medicinal Chemistry May 1, 2012
- Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands. Bioorganic & Medicinal Chemistry Letters May 15, 2013
- A Review of Salvinorin Analogs and their Kappa-Opioid Receptor Activity Bioorganic & Medicinal Chemistry Letters March 12, 2018
- Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse. Advances in pharmacology (San Diego, Calif.) 2014
and 2 more in the library
Cites 5
- Modification of the furan ring of salvinorin A: identification of a selective partial agonist at the kappa opioid receptor. Bioorganic & Medicinal Chemistry February 1, 2009
- Synthetic studies of neoclerodane diterpenes from Salvia divinorum: preparation and opioid receptor activity of salvinicin analogues. Journal of Medicinal Chemistry July 26, 2007
- Synthesis of salvinorin A analogues as opioid receptor probes. Journal of Natural Products June 2006
- Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2). Bioorganic & Medicinal Chemistry Letters June 1, 2005
- Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist. Journal of Medicinal Chemistry January 27, 2005