期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 24, 页码 10464-10475出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501521d
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资金
- National Institute on Drug Abuse [DA018151]
- NIH Dynamic Aspects of Chemical Biology training grant [GM008545]
- Neurological Foundation of New Zealand
- NIH Shared Instrumentation Grant [S10RR024664]
- NSF Major Research Instrumentation Grant [0320648]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0320648] Funding Source: National Science Foundation
The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent kappa-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the kappa-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other kappa-opioid agonists.
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