Synthesis and In Vitro Pharmacological Activity of C-2 Modified New Salvinorin A Analogues

The neoclerodane diterpenoid salvinorin A isolated from the leaves of hallucinogenic sage Salvia divinorum, is a potent and selective κ-opioid receptor (KOR) agonist [1]. Since its discovery, a large number of analogues have been prepared by semi-synthesis to probe the pharmacophore and mode of binding [2]. Some of these analogues present interesting pharmacological profiles from full KOR agonist to partial δ-opioid receptor (DOR) or µ-opioid receptor (MOR) agonist and antagonists. The current objective is to utilize the knowledge about salvinorin A-KOR interactions to rationally design salvinorin A derivatives with different pharmacological profiles and therapeutic potential. In the course of our work on the molecular mechanism of interaction of salvinorin A with KOR, we reported irreversible binding of 22-thiocyanatosalvinorin A with the sulfhydryl group of Cysteine-315 at the κ-opioid receptor [3]. The presence of electron withdrawing group substituents at C-22 may enhance electrophilicity of this center and thereby leads to stronger binding with the thiol group of Cys-315 of KOR. Here we report, a new series of salvinorin A derivatives modified at C-2, and evaluated for their in vitro binding affinity to KOR, MOR and DOR. 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] Roth BL, et al. (2002) Proceedings of the National Academy of Sciences, 99: 11934 – 11939. [2] Cunningham CW, et al. (2011) Pharmacol Rev, 63: 316 – 347. [3] Yan F, et al. (2009) Biochem, 48: 6898 – 6908.