Dissertation

Chemical tools to modulate endocannabinoid biosynthesis

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

Author

Hui Deng

Date

11 April 2017

Links

Thesis in Leiden Repository

The thesis describes the design, synthesis and application of chemical tools to study the physiological roles of DAGLa/b and MAGL in vitro and in vivo. Chapter2 reports on the design, synthesis and in vitro characterization of DH376 as a new dual DAGL inhibitors. In Chapter 3 the discovery of DH379 as a tailor-made activity-based probe for DAGLa/b and the effects of acute pharmacological blockade of DAGLa/b by DH376 in healthy and lipopolysaccharide-treated mice on brain lipid networks and neuroinflammation is described. Chapter 4 reports the efficacy of DH376 in refeeding behavior of fasted mice. In Chapter 5 the development of the first DAGL PET ligand [18F]DH439 is disclosed. The structure-activity relationship of disubstituted piperidinyl ureas as DAGL inhibitors is reported in Chapter 6. The design, synthesis and application of a highly selective tailor-made activity-based imaging probe for MAGL is discussed in Chapter 7.

• activity-based probes
• diacylglycerol-lipases