The Journal of pharmacology and experimental therapeutics
July 1, 2019
Eduardo R Butelman, Bryan D McElroy, Thomas E Prisinzano et al.
Activating the kappa opioid receptor system with the agonist salvinorin A caused dose-dependent decreases in self-grooming behavior in male mice, indicating anhedonia. Two short-acting kappa antagonists, LY2444296 and LY2795050, dose- and time-dependently prevented these grooming deficits. At kappa-selective doses, both antagonists also reduced immobility in the forced swim test, suggesting anti-anhedonia effects. The findings implicate the kappa-receptor system in an ethologically relevant measure of anhedonia and show that these antagonists can produce effects consistent with rapid anti-anhedonia.
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.
Journal of natural products
July 28, 2017
Anil Yilmaz, Rachel Saylor Crowley, Alexander M Sherwood et al.
Columbin, a natural compound from plants used in traditional medicine, was modified to create derivatives that might activate the kappa-opioid receptor (KOR), a target for conditions like anxiety, depression, and addiction. The derivatives showed slightly improved activity at the KOR compared to the original columbin, but neither the parent compound nor its derivatives were potent KOR ligands. This study is the first to test columbin at the KOR and explores chemical modifications that can be made to the columbin molecule.
Neuropharmacology
November 1, 2014
Bronwyn 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 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.
Organic & biomolecular chemistry
September 21, 2009
Denise S Simpson, Kimberly M Lovell, Anthony Lozama et al.
Modifying the furan ring of salvinorin A, the active component of Salvia divinorum, produced new compounds with activity at opioid receptors. A computational study predicted salvinorin A to be a reproductive toxicant in mammals, suggesting its use may have adverse effects. Two new compounds, piperidine 21 and thiomorpholine 23, were identified as selective partial agonists at kappa opioid receptors. This suggests further structural changes could yield ligands with good opioid receptor selectivity but lower toxicity.
Bioorganic & medicinal chemistry letters
November 15, 2007
Kenneth G Holden, Kevin Tidgewell, Alfred Marquam et al.
Removing the C-1 ketone from salvinorin A and its analogue herkinorin changes their activity at opioid receptors. A derivative called 1-deoxo-1,10-dehydrosalvinorin A acts as a moderately potent antagonist at all three opioid receptor subtypes. Herkinorin, a mu opioid agonist, becomes a weak antagonist when its C-1 ketone is removed. These results indicate the C-1 ketone is a key structural feature for mu agonist activity.