Synthesis and biological evaluation of C-2 halogenated analogs of salvinorin A

Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Based on the SAR, its C-2 position is one of the key binding sites and has very little space tolerance (3–4 carbons atoms) and limited to only lipophilic groups. In our attempt to prepare PET brain imaging agent for mapping KOPR, a series of C-2 halogenated analogs have been synthesized and screened for binding affinity at κ (KOPR), μ (MOPR), and δ (DOPR). These C-2 halogenated analogs with sequential changes of atomic radius and electron density serve as excellent molecular probes for further investigating the binding pocket at C-2, particularly on the effects of α verses β configuration at C-2 position. The results of KOPR binding and functional studies reveal β isomer in general binds better than α isomer with the exception of iodinated analogs and none of the C-2 halogenated analogs shows any improvement of KOPR binding affinity. Interestingly, functional assay has characterized that 6b is a partial agonist with Emax of 46% of the kappa receptor full agonist U50,488H at 250 nM (Ki). We have also observed that the affinity to the kappa receptor increases with atomic radius (I > Br > Cl > F) which is in good agreement with halogen bonding interactions reported in the literature.

Graphical abstractWe have carried out the synthesis and biological evaluation of C-2 halogenation analogs of salvinorin A. KOPR binding and functional studies reveal β isomer in general binds better than α isomer and affinity to the kappa receptor increases with atomic radius (I > Br > Cl > F) with the exception of iodinated analog 6b, which is a partial agonist with Emax of 46% of U50,488H.Figure optionsDownload full-size imageDownload as PowerPoint slide