2. Academic Validation
  3. Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

  • Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E5006-E5015. doi: 10.1073/pnas.1704065114.
Andrea Chicca 1,  Simon Nicolussi 1,  Ruben Bartholomäus 2,  Martina Blunder 3 4,  Alejandro Aparisi Rey 5,  Vanessa Petrucci 1,  Ines Del Carmen Reynoso-Moreno 1 6,  Juan Manuel Viveros-Paredes 6,  Marianela Dalghi Gens 1,  Beat Lutz 5,  Helgi B Schiöth 3,  Michael Soeberdt 7,  Christoph Abels 7,  Roch-Philippe Charles 1,  Karl-Heinz Altmann 2,  Jürg Gertsch 8
Affiliations

Affiliations

  • 1 Institute of Biochemistry and Molecular Medicine, National Centre of Competence in Research NCCR TransCure, University of Bern, 3012 Bern, Switzerland.
  • 2 Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland.
  • 3 Department of Neuroscience, Biomedical Center, Uppsala University, 751 24 Uppsala, Sweden.
  • 4 Brain Institute, Universidade Federal do Rio Grande do Norte, Natal 59056-450, Brazil.
  • 5 Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, D-55099 Mainz, Germany.
  • 6 Centro Universitario de Ciencias Exactas e Ingenierías, University of Guadalajara, 44430 Guadalajara, Mexico.
  • 7 Dr. August Wolff GmbH & Co. KG Arzneimittel, 33611 Bielefeld, Germany.
  • 8 Institute of Biochemistry and Molecular Medicine, National Centre of Competence in Research NCCR TransCure, University of Bern, 3012 Bern, Switzerland; [email protected].
PMID: 28584105 DOI: 10.1073/pnas.1704065114
Abstract

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.

Keywords

2-AG; endocannabinoid reuptake; endocannabinoid system; inhibitor; lipid transport.

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