Isolation and Chemical Modification of Clerodane Diterpenoids from Salvia Species as Potential Agonists at the Κ -Opioid Receptor

Abstract

The clerodane diterpenoid salvinorin A ( 1 ), the main active component of the psychotropic herb Salvia divinorum , has been reported to be a potent agonist at the Κ -opioid receptor. Computer modeling suggested that splendidin ( 2 ) from S. splendens , as well as related compounds, might possess similar activities. In the present study, this hypothesis was tested by determination of the binding properties of a series of structural congeners, compounds 2 – 8 , at the Μ -, Δ -, and Κ -opioid receptors. However, none of these compounds showed significant binding to any of the opioid-receptor subtypes, thus disproving the above hypothesis. The novel compounds 7 and 8 were obtained semi-synthetically by selective modification of salvifarin ( 5 ), isolated from Salvia farinacea , upon epoxide-ring opening with AcOH in the presence of indium(III) triflate. Also, the X-ray crystal structure of salvifaricin ( 6 ; Fig. ), obtained from S. farinacea , was determined for the first time and used, in combination with in-depth NMR experiments, to elucidate the absolute configurations of the new products. Our experiments demonstrate that the relatively well-accessible diterpenoid 6 could be used as starting material for future studies into the structure–activity relationship at the Κ -opioid receptor.