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), pp. 6102-6114. Elsevier 10.1016/j.bmc.2017.02.031

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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 10μM. 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Faculty Institutions > NCCR TransCure
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Chicca, Andrea and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0968-0896

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

19 Feb 2018 11:26

Last Modified:

26 Oct 2019 00:55

Publisher DOI:

10.1016/j.bmc.2017.02.031

PubMed ID:

28284861

BORIS DOI:

10.7892/boris.111388

URI:

https://boris.unibe.ch/id/eprint/111388

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