2013 Theses Doctoral

I: Catalytic Direct C-H Arylation of Pyrazoles. II: Toward Modulation of Neuroplasticity with Small Molecules

Jacques, Teresa

Part I of this thesis (Chapter 1) describes the development of the first synthetic method for intermolecular palladium-catalyzed direct C-H arylation of N-substituted pyrazole compounds. The scope of the reaction and the ability to sequentially and selectively arylate specific positions on the azole core to rapidly access highly substituted pyrazoles will be discussed. Part II of this thesis addresses two separate targets to modulate neuroplasticity.

In Chapter 2, the TrkB receptor as a potential target for pharmacological modulation is examined. Its signaling, role in brain disease, and reported agonists and antagonists are reviewed. In addition, our attempts at establishing an assay to assess TrkB activation, as well as our results using the reported agonists and an antagonist in several model cell lines, are discussed.

The third chapter of this work features the development of rationally-designed isoquinuclidines that induce GDNF production by brain cell models. In addition to examining the mechanism of action of an isoquinuclidine (XL-026) using pharmacological inhibition, the mapping of GDNF production and release by C6 rat glioma cells is described and a mechanistic model based on our results is presented.