OPEN Foundation

J. Zjawiony

22-azidosalvinorin A exhibits antidepressant-like effect in mice

February 17, 2017 / Depression, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , ,

Abstract

The increasing cases of depression has made the searches for new drugs and understanding of the underligning neurobiology of this psychiatric disorder a necessity. Here, we modified the structure of salvinorin A (a known halucinogen) and investigated antidepressant-like activity of its four derivatives; 22-methylsulfanylsalvinorin A(SA1), 2-O-cinnamoylsalvinorin B (CSB), 22-azidosalvinorin A (SA2), and 2-O-(4’-azidophenylsulfonyl)salvinorin B (SA3). Prior to behavioural tests (Irwin test, open field test – OFT, forced swimming test – FST and tail suspension test – TST), SA1 was prepared by reacting salvinorin B and methylthioacetic acid with 89% yield; CSB was obtained from the reaction of salvinorin B and cinnamic acid with 92% yield; SA2 was obtained from the reaction of salvinorin B and azidoacetic acid with 81% yield; and SA3 was prepared by reacting salvinorin B with 4-azidophenylsulfonyl chloride with 80% yield. Oral treatment of mice with these derivatives (1–1000 mg/kg) did not elicit toxic sign or death. Unlike SA, SA1, CSB and SA3, treatment with SA2 (5, 10 and 20 mg/kg) decreased the immobility (TST and FST) and swimming time (FST) without altering locomotor activity in OFT. A decrease in the immobility time in TST and FST confirmed antidepressant-like property of SA2. Although p-chlorophenylalanine (serotonin depletor) or WAY100635 (selective 5-HT1A receptor antagonist) did not attenuate effect of SA2, alpha-methyl-para-tyrosine (catecholamine depletor) and prazosin (selective α1-receptor antagonist) attenuated this effect. SA2 mildly inhibited monoamine oxidase and showed affinity for α1A, α1B, α1D and κ-opioid receptor subtypes. In summary, SA2 induced monoamine-mediated antidepressant-like effect.

Fajemiroye, J. O., Prabhakar, P. R., da Cunha, C. L., Costa, E. A., & Zjawiony, J. K. (2017). 22-Azidosalvinorin A exhibits antidepressant-like effect in mice. European Journal of Pharmacology. 10.1016/j.ejphar.2017.02.031
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Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

October 6, 2014 / Chemistry, New substances, Other substances, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , , ,

Abstract

The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.

Polepally, P. R., Setola, V., Vardy, E., Roth, B. L., Mosier, P. D., & Zjawiony, J. (2014). Michael Acceptor Approach to the Design of New Salvinorin A-Based High Affinity Ligands to the Kappa-Opioid Receptor. Planta Medica, 78(5), 818-829. https://dx.doi.org/10.1016/j.ejmech.2014.07.077
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