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Biological evaluation of pyridone alkaloids on the endocannabinoid system

Chicca, Andrea; Berg, Regina; Jessen, Henning J; Marck, Nicolas; Schmid, Fabian; Burch, Patrick; Gertsch, Jürg; Gademann, Karl (2017). Biological evaluation of pyridone alkaloids on the endocannabinoid system. Bioorganic & Medicinal Chemistry, 25(22):6102-6114.

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 CB1 and CB2 receptors 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 10 μM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Life Sciences > Molecular Biology
Life Sciences > Pharmaceutical Science
Life Sciences > Drug Discovery
Life Sciences > Clinical Biochemistry
Physical Sciences > Organic Chemistry
Language:English
Date:2017
Deposited On:03 Apr 2018 12:23
Last Modified:19 Oct 2024 01:34
Publisher:Elsevier
ISSN:0968-0896
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.bmc.2017.02.031
Project Information:
  • Funder: SNSF
  • Grant ID: 200020_163151
  • Project Title: Directing Neurite Outgrowth through Synthetic Natural Products

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