Universiteit Leiden

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Chemical tools to modulate endocannabinoid biosynthesis

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

Hui Deng
11 april 2017
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.