Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system.
The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitors was performed by utilizing a comparative model of the human MGL enzyme. All hit molecules were tested for their potential MGL inhibitory activity, but no compounds were found capable of inhibiting MGL-like enzymatic activity in rat cerebellar membranes. However, these compounds were also tested for their potential FAAH inhibitory activity and five compounds (2-6) inhibiting FAAH were found with IC50 values between 4 and 44 microM. In addition, the hit molecules from the virtual screening of CB2 receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in our FAAH assay, and four active compounds (7-10) were found with IC50 values between 0.52 and 22 microM. Additionally, compound 7 inhibited MGL-like enzymatic activity with an IC50 value of 31 microM.
Saario
Susanna M
SM
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. susanna.saario@uku.fi
Poso
Antti
A
Juvonen
Risto O
RO
Järvinen
Tomi
T
Salo-Ahen
Outi M H
OM
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D063385:Cannabinoid Receptor Modulators / Q000737:chemistry*; D016208:Databases, Factual; D063388:Endocannabinoids; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D008994:Monoacylglycerol Lipases; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases