Mechanisms of Action Underlying Pore-Modifying Allosteric Modulators of the N-methyl-D-aspartate Receptor Restricted; Files & ToC

Abstract

N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated, calcium and sodium-permeant ion channels found ubiquitously throughout the central nervous system. They are important mediators of synaptic plasticity and neuronal excitability. Aberrant function is implicated in numerous neurological disorders such as Alzheimer's Disease, epilepsy, intellectual disability, stroke, and schizophrenia. As a result, there has been significant therapeutical development since the receptor was first identified in the early 1980s. The overarching goal of this project was to determine the mechanisms of action of allosteric modulators that alter single-channel conductance and ionic permeation through the NMDAR. Chapter 1 discusses the receptor’s role in neuronal function, disease, and prior therapeutic development. In Chapter 2, through a medicinal chemistry campaign, a potent and efficacious positive allosteric modulator (PAM) was identified, and Chapter 3 identifies its mechanisms of action. Chapter 4 then compares the single-channel properties of three previously described PAMs with overlapping structural determinants of activity to explain their mechanisms of action. This analysis revealed that one of these PAMs from Chapter 4 alters single-channel amplitude (unitary conductance), and two do not, and reconciles their macroscopic properties by those measured at the single-channel level. Overall, the work presented within identified novel mechanisms of action for NMDARs and began to reveal a structure-function-relationship underlying these activities.

Table of Contents

This table of contents is under embargo until 09 January 2027

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Pharmacology
Keyword	Patch Clamp Pharmacology Ion Channels Allosteric
Committee Chair / Thesis Advisor	Stephen Traynelis, Emory University
Committee Members	John R. Hepler, Emory University Ray Dingledine, Emory University Matthew J.M. Rowan, Emory University Lonnie P. Wollmuth, Stony Brook University

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	File download under embargo until 09 January 2027	2024-10-31 15:20:00 -0400	File download under embargo until 09 January 2027

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions