Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position

Holden, K. G., Tidgewell, K., Marquam, A., Rothman, R. B., Navarro, H., & Prisinzano, T. E. (2007). Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Exploration of the 1-position. Bioorganic and Medicinal Chemistry Letters, 17(22), 6111-6115. DOI: 10.1016/j.bmcl.2007.09.050

Modification of the C-1 ketone of salvinorin A (2a) produces analogues with opioid antagonist properties. Of particular significance is the finding that 1-deoxo-1,10-dehydrosalvinorin A (11a) is a moderately potent antagonist at all three opioid receptor subtypes, and that herkinorin (2b), a M agonist, is converted to a weak antagonist by removal of the C-1 ketone (3b and 11b). These observations suggest that the ketone of 2b is a key structural feature responsible for M agonist activity.