Convenient Synthesis and In Vitro Pharmacological Activity of Thioesters of Salvinorin B

Salvia divinorum is a plant from the mint family that has been used in traditional spiritual practices by the Mazatec Indians of Oaxaca, Mexico. Chewing fresh leaves or smoking dried leaves will produce hallucinogenic-like experiences [1]. These experiences last for an hour and are reported to be potent and intense [2]. The psychoactive component of this plant, the neoclerodane diterpenoid salvinorin A, has been studied intensively as a potent and selective κ-opioid receptor (KOR) agonist [3]. Since its discovery, a large number of analogues have been synthesized [4]. Among these analogs RB-64 (22-thiocyanatosalvinorin A) has high affinity to KOR and is also an irreversible ligand [5]. As part of our continuing efforts to understand ligand-receptor interactions, we designed and synthesized a new series of thioester salvinorin B derivatives and evaluated for their in vitro binding affinity to kappa, mu and delta-opioid receptors.

Acknowledgements: This work was supported by the NIH Grant R01 DA017204 and the NIMH Psychoactive Drug Screening Program (PDSP), UNC at Chapel Hill, NC 27599. References: [1] Valdes LJ, et al. (1983)J Ethanopharmacol, 7: 287 – 312. [2] Sheffler DJ, et al. (2003) Trends Pharmacol Sci, 24: 107 – 109. [3] Roth BL, et al. (2002) Proceedings of the National Academy of Sciences, 99: 11934 – 11939. [4] Cunningham CW, et al. (2011) Pharmacol Rev, 63: 316 – 347. [5] Yan F, et al. (2009) Biochem, 48: 6898 – 6908.