Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist

Abstract

Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.

Scheme 1

^a Reagents: (a) H₂ (1 atm), Pd/C (5%), MeOH, rt; (b) H₂ (4 atm), Rh/C (5%), CH₂Cl₂/MeOH, rt; (c) DIBALH, THF, -78 °C; (d) Et₃SiH, BF₃•Et₂O, CH₂Cl₂, 0 °C.

Scheme 2

^a Reagents: (a) LiSEt, DMPU, 55 °C; (b) Ac₂O, DMAP, pyridine, rt; (c) BH₃, THF, 55 °C; (d) Thiocarbonyldiimidazole, DMF, 90 °C; (e) Bu₃SnH, AIBN, toluene, 80 °C.

Figure 1