Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice

Nicolussi, Simon; Viveros Paredes, Juan Manuel; Gachet Otanez, Maria Salomé; Rau, Mark; Flores-Soto, Mario Eduardo; Blunder, Martina; Gertsch, Jürg (2014). Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice. Pharmacological research, 80, pp. 52-65. Elsevier 10.1016/j.phrs.2013.12.010

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High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel nanomolar inhibitor (EC50 = 290 nM) of cellular uptake of the endocannabinoid anandamide (AEA). Noteworthy, guineensine did not inhibit endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) nor interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier. Activity-based protein profiling showed no inhibition of serine hydrolases. Guineensine also inhibited the cellular uptake of 2-arachidonoylglycerol (2-AG). Preliminary structure–activity relationships between natural guineensine analogs indicate the importance of the alkyl chain length interconnecting the pharmacophoric isobutylamide and benzodioxol moieties for AEA cellular uptake inhibition. Guineensine dose-dependently induced cannabimimetic effects in BALB/c mice shown by strong catalepsy, hypothermia, reduced locomotion and analgesia. The catalepsy and analgesia were blocked by the CB1 receptor antagonist rimonabant (SR141716A). Guineensine is a novel plant natural product which specifically inhibits endocannabinoid uptake in different cell lines independent of FAAH. Its scaffold may be useful to identify yet unknown targets involved in endocannabinoid transport.

Item Type:

Journal Article (Original Article)


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

UniBE Contributor:

Nicolussi, Simon, Viveros Paredes, Juan Manuel, Gachet Otanez, Maria Salomé, Rau, Mark, Gertsch, Jürg


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








Patrizia Catucci

Date Deposited:

23 Jul 2014 17:05

Last Modified:

05 Dec 2022 14:29

Publisher DOI:





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