Planta Med 2013; 79 - P45
DOI: 10.1055/s-0033-1336487

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

PR Polepally 1, K White 2, BL Roth 2, JK Zjawiony 1
  • 1Department of Pharmacognosy, and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677 – 1848, USA
  • 2Department of Pharmacology, School of Medicine and Division of Medicinal Chemistry and Natural Products, School of Pharmacy, NIMH Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, NC 27599, USA

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.