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Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake
Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland..
Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil..ORCID iD: 0000-0002-0066-8217
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 25, E5006-E5015 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2017. Vol. 114, no 25, E5006-E5015 p.
Keyword [en]
endocannabinoid reuptake, 2-AG, inhibitor, endocannabinoid system, lipid transport
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-329659DOI: 10.1073/pnas.1704065114ISI: 000403687300016PubMedID: 28584105OAI: oai:DiVA.org:uu-329659DiVA: diva2:1142789
Funder
Lars Hierta Memorial Foundation
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2017-09-20Bibliographically approved

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Blunder, MartinaSchiöth, Helgi B.

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