Date of Award

1-1-2013

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Chemistry

Content Description

1 online resource (xiv, 166 pages) : illustrations (some color)

Dissertation/Thesis Chair

Li Niu

Committee Members

Alexander Shekhtman, Jayanti Pande, Carla Theimer

Keywords

2, 3-Benzodiazepine compounds, AMPA receptor, Glutamate receptors, Heteromeric channels, Benzodiazepines, Glutamic acid, Neurotransmitter receptors

Subject Categories

Biophysics | Chemistry | Neuroscience and Neurobiology

Abstract

2,3-Benzodiazepin-4-one (BDZ-11) derivatives are a special group of 2,3-benzodiazepine compounds. These compounds have been previously synthesized as AMPA receptor inhibitors, and they are also potential drugs for the treatment of various neurological diseases involving excessive AMPA receptor activity. AMPA receptors are a subtype of glutamate ion channel proteins and are responsible for the majority of excitatory neurotransmission in the mammalian central nervous system. Specifically, they are critically involved in neuronal development and brain activities, including learning and memory. Overstimulation of AMPA receptors is associated with some neurological diseases such as ALS, stroke and Alzheimer's disease. Despite the fact that hundreds of 2,3-benzodiazepine compounds have been synthesized to date, the mechanism of action of these compounds on AMPA receptors at the molecular level is not well understood, and a quantitative structure-activity relationship has not yet been established. Furthermore, there has not been any systematic characterization of the potency and selectivity of these compounds with each of the AMPA receptor subunits. One main problem is that the rate of AMPA receptor channel opening in response to the binding of glutamate occurs in the microsecond time scale, yet the conventional kinetic techniques do not have a sufficient time resolution for a kinetic study of the effect of an inhibitor on the rate of channel opening.

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