Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake.

Chicca, Andrea; Nicolussi, Simon; Bartholomäus, Ruben; Blunder, Martina; Aparisi Rey, Alejandro; Petrucci, Vanessa; Reynoso, Ines del Carmen; Viveros-Paredes, Juan Manuel; Dalghi Gens, Marianela Gisela; Lutz, Beat; Schiöth, Helgi B; Soeberdt, Michael; Abels, Christoph; Charles, Roch-Philippe; Altmann, Karl-Heinz; Gertsch, Jürg (2017). Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 114(25), E5006-E5015. National Academy of Sciences NAS 10.1073/pnas.1704065114

[img] Text
E5006.full.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Chicca, Andrea, Nicolussi, Simon, Petrucci, Vanessa, Reynoso, Ines del Carmen, Dalghi Gens, Marianela Gisela, Charles, Roch-Philippe, Gertsch, Jürg


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




National Academy of Sciences NAS




Barbara Franziska Järmann-Bangerter

Date Deposited:

21 Mar 2018 16:07

Last Modified:

05 Dec 2022 15:10

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

2-AG endocannabinoid reuptake endocannabinoid system inhibitor lipid transport




Actions (login required)

Edit item Edit item
Provide Feedback