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

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• 作者：Simon Nicolussi ; Juan Manuel Viveros-Paredes ; Mar铆a Salom茅 Gachet ; Mark Rau ; Mario Eduardo Flores-Soto ; Martina Blunder ; J眉rg Gertsch
• 关键词：AA ; arachidonic acid ; ABHD ; alpha/beta hydrolase ; AEA ; anandamide ; 2-AG ; 2-arachidonoyl glycerol ; BSA ; bovine serum albumin ; CHCl3 ; chloroform ; CB1 ; cannabinoid receptor type-1 ; CB2 ; cannabinoid receptor type-2 ; CNS ; central nervous system ; CPM ; counts per minute ; COX ; cyclooxygenase ; DMSO ; dimethyl sulphoxide ; DQF-COSY ; double quantum filtered correlation spectroscopy ; EC50  ; =  ; relative IC50 ; the molar concentration of an inhibitor that corresponds to the half maximal (50%) effect midwa
• 刊名：Pharmacological Research
• 出版年：February, 2014
• 年：2014
• 卷：80
• 期：Complete
• 页码：52-65
• 全文大小：1549 K

文摘

High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel 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 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.