Noncovalent Interactions of Silent Agonists Binding to the Nicotinic Acetylcholine Receptor -and- Investigation into Expanding the Substrate Scope and Improving the Efficiency of Organic Photochemical Protecting Groups

Citation

Blunt, Catriona Emily Wilson (2019) Noncovalent Interactions of Silent Agonists Binding to the Nicotinic Acetylcholine Receptor -and- Investigation into Expanding the Substrate Scope and Improving the Efficiency of Organic Photochemical Protecting Groups. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/JYY6-GY46. https://resolver.caltech.edu/CaltechTHESIS:05232019-143649929

Abstract

This dissertation describes two very different projects. The first project focuses on the binding of a silent agonist to a ligand gated ion channel. The second project focuses on the study of development of new longer wavelength photolabile protecting groups for use in a biological setting to enable the spatially and temporally controlled release of biologically active small molecules.

Chapter I introduces ligand gated ion channels and in particular a model of agonist binding at the nicotinic acetylcholine receptor. In addition, the nonsense suppression methodology used to incorporate the non-canonical amino acids required to probe non-covalent binding interactions is detailed. The second chapter details the use of non-canonical amino acids to study the binding of silent agonist NS6740 at the nicotinic acetylcholine receptor α7 subunit and the discovery of a novel hydrogen bond that modulates silent agonist activity.

Chapters III, IV and V focus on efforts to expand the scope of photolabile protecting groups towards designing longer wavelength derivatives. Chapter III introduces the topic of photoremovable protecting groups and details the mechanist background of a quinone methide based photochemical protecting group.

The fourth chapter investigates the use of quinoline and quinolinium derivatives as photochemical quinone methide precursors. Two quinoline derivatives were found to form a quinone methide transient when irradiated. Quinolinium derivatives proved photostable, most likely due to the electron withdrawing nature of the quinolinium.

The final chapter details efforts to improve the photochemical reaction efficiency of quinone photoreduction by using a radical decarboxylation strategy to trap the charge transfer state. Synthesis of two glycine containing quinone compounds is detailed and their photochemistry is evaluated. Both proved to be photostable.

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