Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A.
Katherine M Prevatt-Smith, Kimberly M Lovell, Denise S Simpson, Victor W Day, Justin T Douglas, Peter Bosch, Christina M Dersch, Richard B Rothman, Bronwyn Kivell, Thomas E Prisinzano
MedChemComm December 1, 2011 DOI: 10.1039/C1MD00192B via PubMed
Summary
AI-generated from the abstractA modified compound, initially derived from a potent natural hallucinogen, surprisingly offers a new avenue for treating drug addiction. Scientists hypothesized that slight structural changes could enhance its therapeutic benefits. Through synthesizing and evaluating new versions, particularly focusing on their interaction with opioid receptors and impact on drug-seeking behaviors in rats, a specific analog was identified. This novel compound not only matched the original's potency at key brain receptors but also effectively reduced cocaine-induced drug-seeking. This discovery represents the first instance of such a modified compound demonstrating anti-addictive capabilities.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Salvinorin A |
| Keywords | Drug addiction treatment Treating drug addiction Anti-addictive capabilities Therapeutic benefits Reduced cocaine-induced drug-seeking |
| Citations | 50 |
| Key finding | Compound 5, a C-2 constrained analog of salvinorin A, has affinity and potency at KOP receptors comparable to salvinorin A and attenuates cocaine-induced drug seeking behavior in rats. |
Abstract
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.