Isolation and chemical modification of clerodane diterpenoids from Salvia species as potential agonists at the kappa-opioid receptor.

Salvinorin A, the active component of Salvia divinorum, is a potent kappa-opioid receptor agonist. Computer modeling suggested that splendidin from Salvia splendens and related compounds might have similar activity. However, none of the tested compounds showed significant binding to mu-, delta-, or kappa-opioid receptors, disproving that hypothesis. Two novel compounds were obtained semi-synthetically from salvifarin isolated from Salvia farinacea. The X-ray crystal structure of salvifaricin was determined for the first time and used to elucidate absolute configurations of new products. The relatively accessible diterpenoid salvifaricin could serve as starting material for future structure-activity relationship studies at the kappa-opioid receptor.

Study at a glance

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 kappa-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 mu-, delta-, and kappa-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 kappa-opioid receptor.