ABSTRACT
Introduction Salvinorin A (1a), isolated from the hallucinogenic sage Salvia divinorum,[1] is a potent and selective κ opioid receptor (KOR) agonist.[2] Because it is the rst known non-nitrogenous compound to have biologically signicant actions at mammalian opioid receptors, 1a enables new approaches to studies of endogenous opioid receptor systems. KOR ligands, in particular, have attracted considerable interest because of their eects on mood states.[3-6] Recently, numerous synthetic derivatives of 1a have been prepared and evaluated for activity at opioid receptors. Some potent agonists have been identied which are expected to show increased stability or solubility.[7] Others have increased anity and potency, [8] or altered subtype selectivity.[9] As yet, however, no derivatives of 1a appear to be KOR partial agonists or antagonists, classes of agents that may have utility in the treatment of psychiatric conditions such as depression or mania.[4,5,10]
Salvinorins tend to isomerize under basic conditions. Valdés reported that borohydride reduction of 1a gave an unidentied stereoisomeric byproduct, which could be converted to an undetermined stereoisomer of 1a.[11] e latter compound was subsequently identied by Brown as 8-epi-salvinorin A (1b). [12] Brown also reported that deacetylation of 1a under basic conditions gave 8-epi-salvinorin B (2b), but did not characterize either compound. Several further reports of epimerization at C-8 appeared over the following decade, [13,14] but no characterization data was presented. Valdés later identied the byproduct mentioned above as 8-epi-diol 3.[15] Characterization data was given, but the basis of the structure assignment was not stated.
