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Chemical probes to ...
Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake
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- Chicca, Andrea (författare)
- Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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- Nicolussi, Simon (författare)
- Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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- Bartholomäus, Ruben (författare)
- Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland.
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- Blunder, Martina (författare)
- Uppsala universitet,Funktionell farmakologi,Univ Fed Rio Grande do Norte, Brain Inst, BR-59056450 Natal, RN, Brazil.
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- Rey, Alejandro Aparisi (författare)
- Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany.
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- Petrucci, Vanessa (författare)
- Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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- del Carmen Reynoso-Moreno, Ines (författare)
- Univ 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, Juan (författare)
- Univ Guadalajara, Ctr Univ Ciencias Exactas & Ingn, Guadalajara 44430, Jalisco, Mexico.
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- Gens, Marianela Dalghi (författare)
- Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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- Lutz, Beat (författare)
- Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany.
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- Schiöth, Helgi B. (författare)
- Uppsala universitet,Funktionell farmakologi
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- Soeberdt, Michael (författare)
- Dr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany.
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- Abels, Christoph (författare)
- Dr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany.
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- Charles, Roch-Philippe (författare)
- Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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- Altmann, Karl-Heinz (författare)
- Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland.
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- Gertsch, Jürg (författare)
- Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, CH-3012 Bern, Switzerland.
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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)
- 2017-06-05
- 2017
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:25, s. E5006-E5015
- Relaterad länk:
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https://www.pnas.org...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- endocannabinoid reuptake
- 2-AG
- inhibitor
- endocannabinoid system
- lipid transport
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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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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del Carmen Reyno ...
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Manuel Viveros-P ...
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Gens, Marianela ...
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Lutz, Beat
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Schiöth, Helgi B ...
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Soeberdt, Michae ...
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Abels, Christoph
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Charles, Roch-Ph ...
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Altmann, Karl-He ...
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Gertsch, Jürg
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- MEDICIN OCH HÄLSOVETENSKAP
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Uppsala universitet