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

Abstract

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.