Synthesis and biological evaluation of C-12 triazole and oxadiazole analogs of salvinorin A

Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ-opioid receptor (KOPR) agonist. A series of C-12 triazole analogs and the oxadiazole (4) analog of 1 are synthesized and screened for binding affinity at κ, μ (MOPR), or δ (DOPR). Surprisingly, all triazole analogs have shown negligible binding affinity at opioid receptors and the oxadiazole 4, a reported MOPR and KOPR antagonist, exhibits very low affinities to opioid receptors and no antagonism in our binding assays. These results suggest that electronic factors that may affect either the electron density of hydrogen bond acceptor at C-12 or hydrophobic interactions between C-12 moiety and KOPR are critical to C-12 analog’s affinity for KOPR.

Graphical abstractWe have carried out the synthesis and biological evaluation of C-12 triazole and oxadiazole analogs of salvinorin A. SAR studies suggest that electronic factors that may affect either the electron density of hydrogen bond acceptor at C-12 or hydrophobic interactions between C-12 moiety and KOPR are critical to salvinorin A templated C-12 analog’s affinity for KOPR.Figure optionsDownload full-size imageDownload as PowerPoint slide