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

Abstract	High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel nanomolar inhibitor (EC50=290nM) 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.
Authors	Simon Nicolussi, Juan Manuel Viveros-Paredes, María Salomé Gachet, Mark Rau, Mario Eduardo Flores-Soto, Martina Blunder, Jürg Gertsch
Journal	Pharmacological research (Pharmacol Res) Vol. 80 Pg. 52-65 (Feb 2014) ISSN: 1096-1186 [Electronic] Netherlands
PMID	24412246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References	Alkenes Analgesics Arachidonic Acids Cannabinoid Receptor Antagonists Endocannabinoids Fabp5 protein, mouse Fatty Acid-Binding Proteins Glycerides Heterocyclic Compounds, 2-Ring Neoplasm Proteins Piperidines Polyunsaturated Alkamides Pyrazoles Receptors, Cannabinoid guineensine glyceryl 2-arachidonate Monoacylglycerol Lipases Serhl protein, mouse Serine Endopeptidases Amidohydrolases fatty-acid amide hydrolase Rimonabant anandamide
Topics	Alkenes (administration & dosage, chemistry, pharmacology) Amidohydrolases (metabolism) Analgesics (administration & dosage, pharmacology) Animals Arachidonic Acids (metabolism) Biological Transport (drug effects) Brain (drug effects, enzymology, metabolism) Cannabinoid Receptor Antagonists (pharmacology) Catalepsy (chemically induced) Dose-Response Relationship, Drug Endocannabinoids (metabolism) Fatty Acid-Binding Proteins Glycerides (metabolism) Heterocyclic Compounds, 2-Ring (administration & dosage, chemistry, pharmacology) Humans Hypothermia (chemically induced) Locomotion (drug effects) Male Mice Mice, Inbred BALB C Monoacylglycerol Lipases (metabolism) Neoplasm Proteins Piper (chemistry) Piperidines (pharmacology) Polyunsaturated Alkamides (metabolism) Pyrazoles (pharmacology) Receptors, Cannabinoid (metabolism) Rimonabant Serine Endopeptidases Structure-Activity Relationship U937 Cells

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