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Guineensine Is A Novel Inhibitor Of Endocannabinoid Uptake Showing Cannabimimetic Behavioral Effects

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 a b s t r a c t

High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum asnovel 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 bindingprotein 5 (FABP5), a major cytoplasmic AEA carrier. Activity-based protein profiling showed no inhibitionof serine hydrolases. Guineensine also inhibited the cellular uptake of 2-arachidonoylglycerol (2-AG). Pre-liminary structure–activity relationships between natural guineensine analogs indicate the importance ofthe alkyl chain length interconnecting the pharmacophoric isobutylamide and benzodioxol moieties forAEA cellular uptake inhibition. Guineensine dose-dependently induced cannabimimetic effects in BALB/cmice shown by strong catalepsy, hypothermia, reduced locomotion and analgesia. The catalepsy and anal-gesia were blocked by the CB1 receptor antagonist rimonabant (SR141716A). Guineensine is a novel plantnatural product which specifically inhibits endocannabinoid uptake in different cell lines independent ofFAAH. Its scaffold may be useful to identify yet unknown targets involved in endocannabinoid transport.


The Piper genus is a rich source of bioactive scaffolds asfurther exemplified by the here reported finding of guineen-sine as potent inhibitor of EC cellular uptake. Yangonin from P.methysticum was recently described as a novel ligand of the CB1receptor [59] and kavalactones from the same plant were shownto exert anti-inflammatory effects [86]. Additionally, Piper spp.fruits also contain significant amounts of the sesquiterpene beta-caryophyllene, which is a CB2 receptor agonist [38]. Thus severalPiper-derived compounds are targeting different proteins withinthe ECS.



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