Planta Med 2015; 81 - PC4
DOI: 10.1055/s-0035-1545191

New C(2)-sulfonyl ester-type Salvinorin A ligands to the kappa-opioid receptor

PR Polepally 1, 3, A Keasling 1, K White 2, E Vardy 2, BL Roth 2, JK Zjawiony 1
  • 1Department of BioMolecular Sciences, Division of Pharmacognosy, University of Mississippi, University, MS 38677
  • 2Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599
  • 3Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48108

The neoclerodane diterpenoid salvinorin A is a major metabolite isolated from the leaves of 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. This has encouraged several research groups to study the structure-activity relationships and a plethora of salvinorin A derivatives have been synthesized over the past decade. These analogues exhibit a range of pharmacological profiles from full KOR agonist to partial δ-opioid receptor (DOR) or µ-opioid receptor (MOR) agonists and antagonists. Our current objective is to use the knowledge about salvinorin A-KOR interactions to rationally design salvinorin A derivatives with improved pharmacological profiles and therapeutic potential. Herein, we report the synthesis of a new series of sulfonyl ester-type of salvinorin A derivatives modified at C-2 for improved binding affinity to the KOR. Many of these analogs have shown high affinity (Ki= 6.31 – 130 nM) at KOR and low binding affinity at DOR or MOR.