Planta Med 2015; 81 - PC5
DOI: 10.1055/s-0035-1545192

High affinity C(2)-thiocarbonate and thioacetate-type salvinorin A ligands to the kappa-opioid receptor

PR Polepally 1, 4, A Keasling 1, K White 2, E Vardy 2, PD Mosier 3, 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 Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298
  • 4Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48108

Salvinorin A is a potent and selective κ-opioid receptor (KOR) agonist isolated from the leaves of hallucinogenic sage Salvia divinorum. This natural product exhibits unique biological activity, in that it is the only non-nitrogenous hallucinogen. Since its discovery, a vast number of analogues have been created to probe the pharmacophore and mode of binding. Some of these analogues present a range pharmacological profiles from full KOR agonist to partial δ-opioid receptor (DOR) or µ-opioid receptor (MOR) agonist and antagonists. Structural modifications of salvinorin A at the C-2 position provided compounds with increased affinity. The objective now is to use the knowledge about salvinorin A-KOR interactions to rationally design salvinorin A derivatives with different pharmacological profiles and therapeutic potential. To better understand the ligand-KOR interactions, we report the synthesis, KOR binding affinity and potency of a C(2)-modified series of thiocarbonate and thioacetate-type salvinorin A analogues shown to have significant binding affinity (Ki= 4 – 177 nM) at KOR.