Planta Med 2012; 78 - PI238
DOI: 10.1055/s-0032-1320925

New salvinorin A – Derived ligands to opioid receptors

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

The neoclerodane diterpenoid salvinorin A is a major metabolite isolated from the leaves of psychoactive plant Salvia divinorum. It is a highly selective κ-opioid receptor (KOR) agonist and is the most potent naturally occurring hallucinogen. It gained significant scientific interest, being the only non-nitrogenous KOR agonist with no apparent structural similarity to other ligands. Previously, extensive efforts were made to understand how salvinorin A binds and activates the receptor. Our goal is to design a series of salvinorin A-ligands with high affinity to KOR in order to further explore the ligand-receptor interactions at the molecular level. In continuation of our research towards irreversible ligands, we synthesized a series of new C-2 modified salvinorin A derivatives and evaluated them for binding affinity to opioid receptors. A majority of the analogs have shown high affinity to KOR, and some of them have exhibited dual affinity to κ- and µ-opioid receptors.