Canna~Fangled Abstracts

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

By January 8, 2014No Comments
2014 Jan 8. pii: S1043-6618(14)00002-4. doi: 10.1016/j.phrs.2013.12.010. [Epub ahead of print]

pm8Guineensine 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.
Copyright © 2014. Published by Elsevier Ltd.

KEYWORDS:

(+)-R-WIN 55,212-2 (PubChem CID: 5311501), 2-AG, 2-Arachidonoylglycerol (PubChem CID: 5282280), 2-arachidonoyl glycerol, AA, ABHD, AEA, Anandamide (PubChem CID: 5281969), Anandamide uptake, BSA, CB1, CB2, CHCl(3), CNS, COX, CPM, Cannabimimetic, DMSO, DQF-COSY, EC, EC(50)=relative IC(50), ECS, Endocannabinoid system, Endocannabinoid transport inhibition, EtNH2, EtOAc, FAAH, FABP5, FP, Guineensine, Guineensine (PubChem CID: 6442405), HMBC, HMC-1, HPLC, HSQC, Haloperidol (PubChem CID: 3559), Heteronuclear Multiple Bond Correlation, Heteronuclear Single Quantum Coherence, IC(50)=absolute IC50, JZL184 (PubChem CID: 25021165), LOX, MAGL, NMR, OMDM-2 (PubChem CID: 57347656), Rimonabant (PubChem CID: 104850), SAR, SPE, TLC, U937, UCM707 (PubChem CID: 53394011), URB597 (PubChem CID: 1383884), alpha/beta hydrolase, anandamide, anandamide uptake, arachidonic acid, bovine serum albumin, cannabimimetic, cannabinoid receptor type-1, cannabinoid receptor type-2, central nervous system, chloroform, counts per minute, cyclooxygenase, dimethyl sulphoxide, double quantum filtered correlation spectroscopy, endocannabinoid, endocannabinoid system, endocannabinoid transport inhibition, ethanolamine, ethylacetate, fatty acid amide hydrolase, fatty acid binding protein 5, fluorescence polarization, high pressure liquid chromatography, human leukemia mast cells, human monocytic lymphoma cell line, lipoxygenase, monoacylgylcerol lipase, nuclear magnetic resonance spectroscopy, solid phase extraction, structure-activity relationship, the molar concentration of an inhibitor that corresponds to the half maximal (50%) effect midway between the upper and lower plateaus, the molar concentration of an inhibitor that corresponds to the half maximal (50%) of control response (the mean of the 0% and 100% assay controls), thin layer chromatography

PMID:

 

24412246

 

[PubMed – as supplied by publisher]
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