期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 25, 页码 E5006-E5015出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704065114
关键词
endocannabinoid reuptake; 2-AG; inhibitor; endocannabinoid system; lipid transport
资金
- Swiss National Science Foundation NCCR TransCure
- EIN Roche grant
- F. Hoffmann-La Roche
- Brazilian Research Council
- Fredrik, Ingrid Thurings Stiftelse
- Stiftelse Lars Hiertas
- Ahlen-stiftelse
- Bundesministerium fur Wirtschaft und Energie (ZIM KOOP) [KF2611301MD0]
The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50 = 10 nM) inhibitor N-(3,4-dimethoxyphenyl) ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.
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