Journal article
Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice.
- Nicolussi S Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
- Viveros-Paredes JM Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
- Gachet MS Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
- Rau M Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland.
- Flores-Soto ME Departamento de Farmacobiología CUCEI, Universidad de Guadalajara, 44430 Guadalajara, Jalisco, Mexico.
- Blunder M Department of Neuroscience, Uppsala University, BMC, 751 24 Uppsala, Sweden.
- Gertsch J Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern, Switzerland. Electronic address: gertsch@ibmm.unibe.ch.
- 2014-01-14
Published in:
- Pharmacological research. - 2014
(+)-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)
Alkenes
Amidohydrolases
Analgesics
Animals
Arachidonic Acids
Biological Transport
Brain
Cannabinoid Receptor Antagonists
Catalepsy
Dose-Response Relationship, Drug
Endocannabinoids
Fatty Acid-Binding Proteins
Glycerides
Heterocyclic Compounds, 2-Ring
Humans
Hypothermia
Locomotion
Male
Mice
Mice, Inbred BALB C
Monoacylglycerol Lipases
Neoplasm Proteins
Piper
Piperidines
Polyunsaturated Alkamides
Pyrazoles
Receptors, Cannabinoid
Rimonabant
Serine Endopeptidases
Structure-Activity Relationship
U937 Cells
English
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1016/j.phrs.2013.12.010
- PMID 24412246
- Persistent URL
- https://sonar.rero.ch/global/documents/115237
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