Neoclerodane Diterpenes as Potential Drug Abuse Therapeutics
Kevin Tidgewell,¹ Wayne Harding,¹ Ken Holden,² Christina Dersch,³ Eduardo Butelman,⁴ Richard Rothman,³ and Thomas Prisinzano¹

¹Division of Medicinal & Natural Products Chemistry, The University of Iowa
²Holden Laboratories
³IRP, NIDA, NIH, DHHS
⁴Rockefeller University

Abstract

Purpose: Salvia divinorum is gaining popularity as a legal recreational drug in the United States and Europe. The main active component of the hallucinogenic sage is salvinorin A, a neoclerodane diterpene that has been shown to be a selective and potent k-opioid receptor agonist. Currently however, there is little research into the detailed pharmacokinetic and pharmacodynamic properties of Salvia divinorum, as well as both short and long-term effects of its use. k-Opioid agonists have been shown to antagonize the effects of CNS stimulants by modulating the level of dopamine in the brain. k Antagonists possess utility in the treatment of opioid dependence and have been shown to have anti-depressant activity as well as block stress-induced behavior responses. Salvinorin A thus represents not only a potential drug of abuse but also a possible route for the creation of novel therapeutics for stimulant and opioid dependence.
Methods: Initially, we set out to optimize the extraction of salvinorin A from Salvia divinorum leaves in order to synthesize and evaluate analogues of salvinorin A. For the isolation of salvinorin A, we have modified existing procedures and increased the bio-yield to approximately 7.5 g from 1.5 kg of dried leaves. Analogues were synthesized and tested for opioid receptor affinity using [125I]-IOXY and activity using the [35S]-GTPgS assay.
Results: We have prepared analogues with similar binding affinity at k-opioid receptors and also prepared a non-nitrogenous ligand possessing m-opioid receptor affinity. In addition, we synthesized a deuterated analogue that allows for LC-MS detection of salvinorin A and its metabolites in biological fluids.
Conclusion: The ability to detect salvinorin A in body fluids will allow for the future determination of a metabolic pathway. In addition, analogues with high affinity and selectivity will be further optimized as potential therapeutics.