title: 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.affiliation: Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Nicolussi
authors.affiliation: Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Viveros-Paredes
authors.affiliation: Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: María Salomé
authors.initials: MS
authors.lastname: Gachet
authors.affiliation: Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Rau
authors.affiliation: Departamento de Farmacobiología CUCEI, Universidad de Guadalajara, 44430 Guadalajara, Jalisco, Mexico.
authors.forename: Mario Eduardo
authors.initials: ME
authors.lastname: Flores-Soto
authors.affiliation: Department of Neuroscience, Uppsala University, BMC, 751 24 Uppsala, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Blunder
authors.affiliation: Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland. Electronic address: gertsch@ibmm.unibe.ch.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
mesh_terms: D000475:Alkenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000581:Amidohydrolases / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins; D005989:Glycerides / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D009363:Neoplasm Proteins; D031701:Piper / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism; D000077285:Rimonabant; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D020298:U937 Cells; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000475:Alkenes; D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D050556:Fatty Acid-Binding Proteins; D005989:Glycerides; D006574:Heterocyclic Compounds, 2-Ring; D008994:Monoacylglycerol Lipases; D009363:Neoplasm Proteins; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D000077285:Rimonabant; D012697:Serine Endopeptidases; D000099252:Fatty Acid Amide Hydrolases; C082667:Fabp5 protein, mouse; C492480:guineensine; C094503:glyceryl 2-arachidonate; C431704:Serhl protein, mouse; C078814:anandamide
keywords: (+)-R-WIN 55,212-2 (PubChem CID: 5311501); 2-Arachidonoylglycerol (PubChem CID: 5282280); Anandamide (PubChem CID: 5281969); Anandamide uptake; Cannabimimetic; Endocannabinoid system; Endocannabinoid transport inhibition; Guineensine; Guineensine (PubChem CID: 6442405); Haloperidol (PubChem CID: 3559); JZL184 (PubChem CID: 25021165); OMDM-2 (PubChem CID: 57347656); Rimonabant (PubChem CID: 104850); UCM707 (PubChem CID: 53394011); URB597 (PubChem CID: 1383884)