Planta Med 2013; 79 - P41
DOI: 10.1055/s-0033-1336483

New Michael Acceptor-type of Salvinorin A Ligands to Kappa-Opioid Receptor

PR Polepally 1, V Setola 2, E Vardy 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

Salvia divinorum (Lamiaceae) has drawn much attention in recent years due to its psychopharmacological properties. The active ingredient salvinorin A, is a potent κ-opioid receptor (KOR) agonist [1]. Since its discovery, numerous synthetic analogues of salvinorin A have been reported at KOR, µ-opioid receptor (MOR) and δ-opioid receptor (DOR) [2]. The current objective is to use the knowledge about salvinorin A-KOR interactions to rationally design salvinorin A derivatives with different pharmacological profiles and therapeutic potential. Previous work on the KOR model and analysis of the mode of binding of RB-64 (22-thiocyanatosalvinorin A) suggest that Cys-315 may be a good anchoring amino acid at the binding site in KOR [3]. Considering the fact that Michael acceptors may strongly bind with thiol group of Cys-315 of KOR, we synthesized a series of Michael-acceptor type of salvinorin A derivatives, and evaluated for their binding affinity at κ-, µ-, and δ-opioid receptors.

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: [1] Roth BL, et al. (2002) Proc Natl Acad Sci, 99: 11934 – 11939. [2] Cunningham CW et al. (2011) Pharmacol Rev, 63: 316 – 347. [3] Yan F, et al. (2009) Biochemistry, 48: 6898 – 6908.