A variety of plant-derived psychoactive products such as Salvia divinorum, peyote cactus, and Datura stramonium are readily available to the general public and unregulated by the FDA or DEA. Since these products are natural, much of the public may assume that they are safe. However, the abuse potential and health risks of these psychoactive natural products have not been adequately studied, especially the newly emerged S. divinorum. Thus, there is an urgent need to investigate the active components, their metabolites, and mechanisms of action. S. divinorum is often smoked and absorbed through the lungs. It is conceivable that the initial metabolism of smoked salvinorin A, the major bioactive compound isolated from S. divinorum, takes place in the lung, whereas orally consumed salvinorin A may take place in the liver. The proposed isolation and characterization of new metabolites is to provide much needed information on whether metabolites are active or not, and how these metabolites are stored in and disposed of by the body. The overall objective of this application is to focus on the isolation, extraction, and characterization of bioactive compounds and metabolites of S. divinorum and to understand mechanisms of action through in vitro receptor binding and functional assays and in vivo tests.
Our specific aims are 1) to continue our comprehensive isolation and characterization of other potential k-active ligands in S. divinorum;2) to investigate the active smoke degradation products of S. divinorum;3) to investigate the absorption, distribution, and metabolism aspects of the identified products;4) to characterize in vitro and in vivo pharmacological activities of salvinorin A and its analogs and metabolites. A better understanding of k specific natural products isolated from S. divinorum and its metabolites may provide an opportunity for the discovery of novel ligands and the development of potential pharmacotherapies for treating drug addiction and other neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019688-04
Application #
7615517
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (03))
Program Officer
Hillery, Paul
Project Start
2006-09-15
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$276,845
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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Lee, David Y W; Yang, Lu; Xu, Wei et al. (2010) Synthesis and biological evaluation of C-2 halogenated analogs of salvinorin A. Bioorg Med Chem Lett 20:5749-52
Ma, Zhongze; Deng, Gang; Lee, David Y W (2010) Novel neoclerodane diterpene derivatives from the smoke of salvinorin A. Tetrahedron Lett 51:5207-5209
Yang, Lu; Xu, Wei; Chen, Feng et al. (2009) Synthesis and biological evaluation of C-12 triazole and oxadiazole analogs of salvinorin A. Bioorg Med Chem Lett 19:1301-4
Ma, Zhongze; Lee, David Y W (2008) Synthesis of deacetyl-1,10-didehydrosalvinorin G. Tetrahedron Lett 49:1782-1785
Wang, Yulin; Chen, Yong; Xu, Wei et al. (2008) 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A. J Pharmacol Exp Ther 324:1073-83
Ma, Zhongze; Lee, David Y W (2007) Revised structure of deacetyl-1,10-didehydrosalvinorin G. Tetrahedron Lett 48:5461-5464