Synthesis and In Vitro Biological Evaluation of New Dicarboxylic Ester-type Salvinorin A Analogs
Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen . It is a highly selective kappa-opioid receptor (KOR) agonist . To better understand the ligand-receptor interactions, a new series of dicarboxylic ester type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ, δ, and µ-opioid receptors. Most of the analogs have shown high affinity to κ-opioid receptor. Methyl malonyl derivative has shown higher binding affinity than parent compound salvinorin A at KOR. The ethyl malonyl ligand, methyl succinyl analog and methyl fumaryl derivative have also shown significant affinity for κ-receptor.
Acknowledgements: This work was supported by the NIH Grant R01 DA017204 and the NIMH Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill, NC 27599. References:  Valdes LJ, et al. (1983)J Ethnopharmacol, 7: 287 – 312.  Roth BL, et al. (2002) Proceedings of the National Academy of Sciences, 99: 11934 – 11939.