Article

Alpha-methylated derivatives of 2-arachidonoyl glycerol: synthesis, CB1 receptor activity, and enzymatic stability.

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.34). 06/2006; 16(9):2437-40. DOI: 10.1016/j.bmcl.2006.01.101
Source: PubMed

ABSTRACT Alpha-methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPgammaS binding assay, and the enzymatic stability of alpha-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the alpha-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.

1 Bookmark
 · 
112 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of endogenous fatty acid amides and their analogues (1-78) were prepared, and their inhibitory effects on pro-inflammatory mediators (NO, IL-1β, IL-6, and TNF-α) in LPS-activated RAW264.7 cells were evaluated. Their inhibitory activity on the pro-inflammatory chemokine MDC in IFN-γ-activated HaCaT cells was also examined. The results showed that the activity is strongly dependent on the nature of the fatty acid part of the molecules. As expected, the amides derived from enone fatty acids showed significant activity and were more active than those derived from other types of fatty acids. A variation of the amine headgroup also altered bioactivity profile remarkably, possibly by modulating cell permeability. Regarding the amine part of the molecules, N-acyl dopamines exhibited the most potent activity (IC(50) ∼2 μM). This is the first report of the inhibitory activity of endogenous fatty acid amides and their analogues on the production of nitric oxide, cytokines (IL-1β, IL-6, and TNF-α) and the chemokine MDC. This study suggests that the enone fatty acid-derived amides (such as N-acyl ethanolamines and N-acyl amino acids) and N-acyl dopamines may be potential anti-inflammatory leads.
    Bioorganic & medicinal chemistry 02/2011; 19(4):1520-7. · 2.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Research on the chemistry and pharmacology of cannabinoids and endocannabinoids has reached enormous proportions, with approximately 15,000 articles on Cannabis sativa L. and cannabinoids and over 2,000 articles on endocannabinoids. The present review deals with the history of the Cannabis sativa L. plant, its uses, constituent compounds and their biogeneses, and similarity to compounds from Radula spp. In addition, details of the pharmacology of natural cannabinoids, as well as synthetic agonists and antagonists are presented. Finally, details regarding the pioneering isolation of the endocannabinoid anandamide, as well as the pharmacology and potential therapeutic uses of endocannabinoid congeners are presented.
    Medicinal Research Reviews 10/2008; 29(2):213-71. · 9.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of endogenous cannabinoids has provided a basis for understanding the structural requirements for activation of the two known cannabinoid receptors CB1 and CB2. The endocannabinoids are fatty acid analogs represented by N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG). These endogenous ligands are biosynthesized and deactivated by a number of enzymes and a transporter system, all of which can be modulated by ligands whose structures can encompass the essential endocannabinoid features. For this reason a significant amount of work has sought to develop synthetic ligands structurally related to AEA and 2-AG. These ligands are being used to explore the structural features of the different cannabinergic proteins and have also proven to be valuable pharmacological tools for studying the physiology and biochemistry of the endocannabinoid system. KeywordsEndocannabinoid-Anandamide-AEA-2-Arachidonoylglycerol-2-AG-Cannabinoid receptors-Structure–activity relationship-Retroanandamide-FAAH inhibitors-AEA transport inhibitors
    12/2008: pages 21-48;

Full-text

View
68 Downloads
Available from
May 28, 2014