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

Abstract

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.