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Chemical probes to ...
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Chicca, AndreaUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
(author)
Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake
- Article/chapterEnglish2017
Publisher, publication year, extent ...
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2017-06-05
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NATL ACAD SCIENCES,2017
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-329659
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-329659URI
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https://doi.org/10.1073/pnas.1704065114DOI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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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Nicolussi, SimonUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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Bartholomäus, RubenSwiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland.
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Blunder, MartinaUppsala universitet,Funktionell farmakologi,Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil.(Swepub:uu)marbl960
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Rey, Alejandro AparisiJohannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany.
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Petrucci, VanessaUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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del Carmen Reynoso-Moreno, InesUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.;Univ Guadalajara, Ctr Univ Ciencias Exactas & Ingn, Guadalajara 44430, Jalisco, Mexico.
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Manuel Viveros-Paredes, JuanUniv Guadalajara, Ctr Univ Ciencias Exactas & Ingn, Guadalajara 44430, Jalisco, Mexico.
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Gens, Marianela DalghiUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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Lutz, BeatJohannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany.
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Schiöth, Helgi B.Uppsala universitet,Funktionell farmakologi(Swepub:uu)helgschi
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Soeberdt, MichaelDr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany.
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Abels, ChristophDr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany.
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Charles, Roch-PhilippeUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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Altmann, Karl-HeinzSwiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland.
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Gertsch, JürgUniv Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
(author)
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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.
(creator_code:org_t)
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In:Proceedings of the National Academy of Sciences of the United States of America: NATL ACAD SCIENCES114:25, s. E5006-E50150027-84241091-6490
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Chicca, Andrea
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Nicolussi, Simon
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Bartholomäus, Ru ...
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Blunder, Martina
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Rey, Alejandro A ...
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Petrucci, Vaness ...
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Manuel Viveros-P ...
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Schiöth, Helgi B ...
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Soeberdt, Michae ...
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Abels, Christoph
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