title: Biological evaluation of pyridone alkaloids on the endocannabinoid system.
abstract: Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1and CB2receptors led to the identification of a compound binding selectively to CB1(12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10μM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.
authors.affiliation: NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chicca
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Berg
authors.affiliation: Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
authors.forename: Henning J
authors.initials: HJ
authors.lastname: Jessen
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Marck
authors.affiliation: Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schmid
authors.affiliation: Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Burch
authors.affiliation: NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland. Electronic address: juerg.gertsch@ibmm.unibe.ch.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: karl.gademann@uzh.ch.
authors.forename: Karl
authors.initials: K
authors.lastname: Gademann
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D063388:Endocannabinoids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020298:U937 Cells; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000470:Alkaloids; D000581:Amidohydrolases; D001095:Arachidonic Acids; D051546:Cyclooxygenase 2; D063388:Endocannabinoids; D008994:Monoacylglycerol Lipases; D053284:Polyunsaturated Alkamides; D011728:Pyridones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide