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

Abstract

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 E(max) of 46% of the kappa receptor full agonist U50,488H at 250 nM (K(i)). 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.

Fig. 1

Scheme 1

Reagents and conditions: (a) Deoxo-Fluor reagent, CH2Cl2, −78 °C, 2 h, rt, 2 h, 3b (74%), 3a (80%); (b) TCT, DMF/CH₂Cl₂, 35 °C, 12 h, 4b (90%), 4a (81%); (c) TCT,DMF/CH₂Cl₂, rt, 2 h; yield varies according to reaction time.

Scheme 2

Reagents and conditions: (a) TCT, DMF/CH₂Cl2, NaBr, overnight, 92%, 4b:5b = 3:2; (b) PBr₃, C₆H₆, rt, 86%; (c) PPh₃, Br₂, imidazole, toluene, 48%; (d) (i) (CF₃SO₂)₂O, pyridine, CH₂Cl₂, 0 °C; (ii) NaBr, DMF, rt, 75% in two-steps.

Scheme 3

Reagents and conditions: (a) I₂, PPh₃, imidazole, Toluene, 80 °C, 1 h, 92–95%; (b) LiI, DMF, rt, overnight, 95%.