Journal of Medicinal Chemistry
December 26, 2014
Andrew P Riley, Chad E Groer, David Young et al.
115 citations
Salvinorin A, a compound from the leaves of Salvia divinorum, activates κ-opioid receptors and could be a basis for treating substance abuse. Researchers synthesized several derivatives with modified furan rings to better understand how this part of the molecule binds to the receptor. Functional assays showed that smaller substitutions are preferred, indicating the furan ring fits into a tight part of the binding pocket. The most potent analogue reduced drug-seeking behavior in an animal model of relapse without causing sedation, a common side effect of other κ-opioid agonists.
Pharmacology, biochemistry, and behavior
December 1, 2009
Aashish S Morani, Bronwyn M Kivell, Thomas E Prisinzano et al.
91 citations
Pretreatment with several kappa-opioid receptor agonists, including salvinorin A (Sal A), the active compound in Salvia divinorum, reduced cocaine-induced drug-seeking in rats. After learning to self-administer cocaine, rats underwent extinction and then received a cocaine priming injection. Cocaine-induced reinstatement of drug-seeking was attenuated by U69593, U50488H, spiradoline, and Sal A. Sal A did not affect sucrose-reinforced responding or cocaine-induced hyperactivity, suggesting its effects are specific to drug-seeking. These findings indicate that Sal A, like other kappa-opioid agonists, can suppress cocaine-seeking behavior.
MedChemComm
December 1, 2011
Katherine M Prevatt-Smith, Kimberly M Lovell, Denise S Simpson et al.
50 citations
A modified compound, initially derived from a potent natural hallucinogen, surprisingly offers a new avenue for treating drug addiction. Scientists hypothesized that slight structural changes could enhance its therapeutic benefits. Through synthesizing and evaluating new versions, particularly focusing on their interaction with opioid receptors and impact on drug-seeking behaviors in rats, a specific analog was identified. This novel compound not only matched the original's potency at key brain receptors but also effectively reduced cocaine-induced drug-seeking. This discovery represents the first instance of such a modified compound demonstrating anti-addictive capabilities.
Molecules (Basel, Switzerland)
October 11, 2018
Bronwyn M Kivell, Kelly F Paton, Nitin Kumar et al.
45 citations
A potent and selective kappa opioid receptor (KOPr) analogue of Salvinorin A, Mesyl Sal B, reduces cocaine-induced hyperactivity and behavioral sensitization to cocaine in male rats without causing aversion, sedation, anxiety, or learning and memory deficits. It does not alter sucrose self-administration. However, it increases immobility in the forced swim test, indicating pro-depressive effects. In male mice, Mesyl Sal B is less potent than Salvinorin A at reducing pain in antinociceptive assays. The compound has fewer side effects and longer in vivo action than Salvinorin A, but its pain-relieving effects are limited.
Journal of Psychoactive Drugs
January 1, 2016
Fiona Hutton, Bronwyn M Kivell, Otis Boyle
5 citations
Salvia divinorum, an intense hallucinogen, was legal in New Zealand when an anonymous questionnaire was advertised to young adults in 2010-2011. Of 393 respondents, 167 had used salvia. Thematic analysis of open-ended answers identified three themes: salvia's effects, the importance of set and setting, and pleasure or not-pleasure from use. Recreational salvia use occurred within a broader drug landscape; participants were drug experienced and "drug wise." Use was intermittent, often described as a novel experience. The 2014 criminalization of salvia under the Psychoactive Substances Amendment Act may lead to a significant decline in use as experienced users seek novel drug experiences elsewhere.
Frontiers in Pharmacology
January 1, 2022
Kelly F Paton, Dan Luo, Anne C La Flamme et al.
Kappa opioid receptor (KOR) agonists, including analogues of Salvinorin A, reduced pain in a mouse model of chemotherapy-induced neuropathic pain. 16-Ethynyl SalA was more potent than morphine at reducing mechanical allodynia, and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. Sex differences appeared in mechanical allodynia testing: U50,488 was more potent in males, SalA more potent in females, but no sex differences occurred in cold allodynia. Chronic U50,488 (10 mg/kg) restored mechanical and cold pain responses to healthy levels over 23 days. KOR agonists may be developed to treat this condition.
Psychopharmacology
August 1, 2017
Amy W M Ewald, Peter J Bosch, Aimee Culverhouse et al.
Two novel analogues of salvinorin A, EOM Sal B and β-THP Sal B, were tested in rats for their ability to reduce cocaine-related behaviors and their side effects. EOM Sal B dose-dependently reduced drug-seeking behavior in a reinstatement model and, along with β-THP Sal B, attenuated cocaine-induced hyperactivity without affecting general locomotion. Neither compound produced anxiety-like or depressive-like effects in the elevated plus maze or forced swim tests. However, β-THP Sal B caused aversion in the conditioned place aversion test. EOM Sal B showed no effect on sucrose self-administration, indicating selectivity for cocaine-related behaviors. EOM Sal B was more potent than salvinorin A and β-THP Sal B with fewer side effects.
Neuropharmacology
November 1, 2014
Bronwyn M Kivell, Zeljko Uzelac, Santhanalakshmi Sundaramurthy et al.
Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, increases dopamine transporter (DAT) activity in cells and rat striatum, which reduces dopamine signaling. This effect is mediated by KOR activation and the ERK1/2 pathway, and involves physical interaction between KOR and DAT proteins. SalA also decreases serotonin transporter activity but does not affect norepinephrine transporter activity. The enhanced dopamine transport, combined with reduced dopamine release, may contribute to the dysphoric and pro-depressant effects of SalA and other KOR agonists.
Advances in pharmacology (San Diego, Calif.)
January 1, 2014
Bronwyn M Kivell, Amy W M Ewald, Thomas E Prisinzano
Salvinorin A, a compound from the plant Salvia divinorum, activates kappa-opioid receptors and reduces drug-seeking behaviors by regulating dopamine levels, similar to traditional kappa-opioid agonists but with fewer side effects like sedation and depression. However, its rapid metabolism limits clinical use. Newer analogs based on Salvinorin A's structure show improved pharmacokinetics and retain anti-addictive effects, offering promise for developing addiction treatments.
European Journal of Pharmacology
November 15, 2013
Aashish S Morani, Amy W M Ewald, Katherine M Prevatt-Smith et al.
Activating the κ opioid receptor with the salvinorin A analogue 2-methoxy-methyl salvinorin B (MOM Sal B) at 0.3 mg/kg reduced cocaine-seeking behavior in rats, but also reduced sucrose reinforcement. No sedation was observed—locomotion in cocaine-induced hyperactivity and open field tests was unchanged—yet the forced swim test showed increased immobility and decreased swimming times, indicating pro-depressive effects. The compound thus modulates cocaine-seeking non-selectively without sedation, but depressive side effects may limit its therapeutic use.