Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A

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Issue Date
2011-12Author
Prevatt-Smith, Katherine M.
Lovell, Kimberly M.
Simpson, Denise S.
Day, Victor W.
Douglas, Justin T.
Bosch, Peter
Dersch, Christina M.
Rothman, Richard B.
Kivell, Bronwyn
Prisinzano, Thomas E.
Publisher
Royal Society of Chemistry
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
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Show full item recordAbstract
Previous structure-activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency at KOP receptors. However, the reason for this increase remains unclear. Here we report our efforts towards the synthesis and evaluation of C-2 constrained analogs of salvinorin A. These analogs were evaluated at opioid receptors in radioligand binding experiments as well as in the GTP-γ-S functional assay. One compound, 5, was found to have affinity and potency at κ opioid (KOP) receptors comparable to salvinorin A. In further studies, 5 was found to attenuate cocaine-induced drug seeking behavior in rats comparably to salvinorin A. This finding represents the first example of a salvinorin A analog that has demonstrated anti-addictive capabilities.
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Citation
Prevatt-Smith, K. M., Lovell, K. M., Simpson, D. S., Day, V. W., Douglas, J. T., Bosch, P., … Prisinzano, T. E. (2011). Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A. MedChemComm, 2(12), 1217–1222. http://doi.org/10.1039/C1MD00192B
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