Biological evaluation of pyridone alkaloids on the endocannabinoid system

Andrea Chicca; Regina Berg; Henning J Jessen; Nicolas Marck; Fabian Schmid; Patrick Burch; Jürg Gertsch; Karl Gademann

doi:10.1016/j.bmc.2017.02.031

Biological evaluation of pyridone alkaloids on the endocannabinoid system

Bioorg Med Chem. 2017 Nov 15;25(22):6102-6114. doi: 10.1016/j.bmc.2017.02.031. Epub 2017 Feb 17.

Authors

Andrea Chicca¹, Regina Berg², Henning J Jessen³, Nicolas Marck², Fabian Schmid³, Patrick Burch³, Jürg Gertsch⁴, Karl Gademann⁵

Affiliations

¹ NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland.
² Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
³ Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
⁴ NCCR-TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland. Electronic address: juerg.gertsch@ibmm.unibe.ch.
⁵ Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: karl.gademann@uzh.ch.

PMID: 28284861
DOI: 10.1016/j.bmc.2017.02.031

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemistry*
Alkaloids / metabolism
Amidohydrolases / antagonists & inhibitors
Amidohydrolases / metabolism
Arachidonic Acids / chemistry
Arachidonic Acids / metabolism
Cyclooxygenase 2 / metabolism
Endocannabinoids / chemistry
Endocannabinoids / metabolism
Humans
Inhibitory Concentration 50
Kinetics
Monoacylglycerol Lipases / antagonists & inhibitors
Monoacylglycerol Lipases / metabolism
Polyunsaturated Alkamides / chemistry
Polyunsaturated Alkamides / metabolism
Protein Binding
Pyridones / chemistry*
Pyridones / metabolism
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Cannabinoid, CB2 / antagonists & inhibitors*
Receptor, Cannabinoid, CB2 / metabolism
U937 Cells

Substances

Alkaloids
Arachidonic Acids
Endocannabinoids
Polyunsaturated Alkamides
Pyridones
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
Cyclooxygenase 2
Monoacylglycerol Lipases
Amidohydrolases
fatty-acid amide hydrolase
anandamide