Planta Med 2012; 78 - P_93
DOI: 10.1055/s-0032-1307601

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

PR Polepally 1, V Setola 2, E Vardy 2, BL Roth 2, PD Mosier 3, J 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
  • 3Department of Medicinal Chemistry, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298–0540, USA

Psychoactive natural products have been used to study the intricate workings of various receptor systems in the central nervous system (CNS). Our studies focused on the identification of plant metabolites responsible for CNS activity and designing new ligands with high affinity to CNS receptors. Salvinorin A, the most potent naturally occurring hallucinogen isolated from the plant Salvia divinorum, has received great attention since the kappa-opiod receptor (KOR) was identified as its molecular target. Previously, extensive efforts were made to understand how salvinorin A binds to and activates KOR [1–5]. Our goal is to design a series of ligands with high affinity to KOR to further explore the ligand-receptor interactions at the molecular level. In continuation of our research work towards designing irreversible ligands [4,5], we synthesized a series of Michael acceptor type of new salvinorin A derivatives and evaluated their binding affinity to KOR, MOR and DOR.

References: [1] Roth BL, et al. (2002) Proc Natl Acad Sci 99: 11934–11939. [2] Yan F, et al. (2005) Biochemistry 44: 8643–8651. [3] Vortherms TA, et al. (2007)J Biol Chem 281: 3146–3156. [4] Yan F, et al. (2008) Biochemistry 47: 1567–1568. [5] Yan F, et al. (2009) Biochemistry 47: 6898–6908.