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Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels

Citation

Blom, Antoinette Elisabeth Maria (2019) Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/RG56-G044. https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414

Abstract

This dissertation describes studies of activation of neuronal ion channels and evaluating new ligands to modulate this process. In chapter two, we expanded the binding model of cytisine to the α4β2 nicotinic acetylcholine receptor. We also determined how C(10)-modification of cytisine impacts the key binding interactions between cytisine and its binding site. To achieve this, we used non-canonical amino acid mutagenesis to probe the electrostatic binding interactions of a novel series of C(10)-cytisine derivatives. In order to perform similar studies in the α3β4 nAChR subtype, we describe the heterologous expression of mouse and human α3β4 nAChRs in Xenopus Laevis oocytes in appendix one. Chapter three describes the development and functional evaluation of a novel series of pyrrolidinoindolines for agonism and modulation of the GABAA receptor. Additionally, we performed mutagenesis studies to identify the binding site of these novel ligands. Appendix two describes a different screen for activation or modulation of GABAA receptors using a set of phenolic compounds implicated in Autism Spectrum Disorder. Chapter four shifts focus to voltage-gated ion channels: in this chapter, the ultimate goal was to photochemically control the activation of VGSCs and make progress towards developing a RubpyC17-based photoswitch that could be used in an artificial retina. To this end, we determined the functional effects of several ruthenium bipyridine analogs on voltage-gated sodium and potassium channels.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:nAChR; cytisine; GABAA; receptor; neuroscience; nicotinic receptor
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dougherty, Dennis A.
Thesis Committee:
  • Rees, Douglas C. (chair)
  • Dougherty, Dennis A.
  • Shapiro, Mikhail G.
  • Reisman, Sarah E.
Defense Date:30 May 2019
Record Number:CaltechTHESIS:06072019-145818414
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:06072019-145818414
DOI:10.7907/RG56-G044
ORCID:
AuthorORCID
Blom, Antoinette Elisabeth Maria0000-0002-7441-4893
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11716
Collection:CaltechTHESIS
Deposited By: Antoinette Blom
Deposited On:10 Jun 2019 22:48
Last Modified:25 May 2021 23:40

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