Design, Synthesis, and Biological Evaluation of Subunit-Selective N-Methyl-D-Aspartate Receptor Antagonists Öffentlichkeit
Mosley, Cara Amelia (2009)
Published
Abstract
Abstract
Design, Synthesis, and Biological Evaluation of
Subunit-Selective
N-Methyl-D-Aspartate Receptor Antagonists
Part 1: Design, Synthesis, and Biological Evaluation of Novel
NR1/NR2B-Selective NMDA
Receptor Antagonists Towards the Treatment of Neurodegenerative
Diseases
Part 2: Design, Synthesis, and Biological Evaluation of
First-in-Class NR2C/2D-Selective
NMDA Receptor Antagonists
By Cara A. Mosley
Part 1:
N-Methyl-D-Aspartate (NMDA)-selective glutamate receptors are
ligand-gated ion channels that mediate a Ca2+-permeable component
of excitatory
synaptic transmission in the central nervous system. The receptors
are tetrameric
complexes, of which there are four different subtypes (NR2A, NR2B,
NR2C and NR2D). Over-activation of NMDA
receptors has been associated with a number of neurodegenerative
diseases in both
animal and human models including stroke, traumatic brain injury,
epilepsy,
schizophrenia, and neuropathic pain. As a potential treatment for
these disorders, a
number of NMDA receptor antagonists have been developed.
In Chapter 1, the synthesis and structure activity relationship
analysis of novel
enantiomeric propanolamines are presented. Compounds have been
evaluated for
potency against the NR1/NR2B subunit of the N-Methyl-D-Aspartate
(NMDA) receptor.
In addition, the pH sensitivity (fold shift) of the analogues is
discussed. Fold shift, i.e. the
increased potency of a given compound at more acidic pH values,
is hypothesized to be
beneficial under ischemic conditions associated with stroke. In
addition, the
compounds described have been specifically designed to exhibit
decreased off-target
activity at the human-ether-a-go-go related gene (hERG) ion
channel, which is often
associated with cardiotoxicity in vivo.
In Chapter 2, a novel series of amide-based NR1/NR2B-selective NMDA
receptor
antagonists is described. Originating in a screening hit
characterized by a
thiosemicarbazide linker region, development of structure activity
relationships led to a
novel series of antagonists characterized by an amide scaffold.
Analogue design is targeted towards inducing pH
sensitivity and eliminating off-target effects. Some of the studied
compounds are
potent, selective, non-competitive, and voltage-independent
antagonists of NR2B-
containing NMDA receptors. Like the founding member of this class
of antagonists
(ifenprodil), several interesting compounds of the series bind to
the amino terminal
domain of the NR2B subunit to inhibit function. Analogue potency is
modulated by
Table of Contents
TABLE OF CONTENTS
List of Illustrations
Figures
Tables
Schemes
Graphs
Charts
List of Abbreviations
Part 1: Design, Synthesis, and Biological Evaluation of Novel
NR1/NR2B-
Selective NMDA Receptor Antagonists Towards Treatment of
Neurodegenerative Diseases
CHAPTER 1
1
1.1 STATEMENT OF PURPOSE
1
1.2 INTRODUCTION AND BACKGROUND
4
1.3 SYNTHESIS OF ENANTIOMERIC PROPANOLAMINE ANALOGUES
31
1.4 PKA DETERMINATION OF NMDA RECEPTOR CHANNEL
BLOCKERS
34
1.5 RESULTS AND DISCUSSION
38
1.6 CHEMISTRY EXPERIMENTAL DETAIL
45
1.7 BIOLOGY EXPERIMENTAL DETAIL
57
CHAPTER 2
68
2.1 STATEMENT OF PURPOSE
68
2.2 INTRODUCTION AND BACKGROUND
70
2.3 SYNTHESIS OF HYDRAZIDE-BASED ANALOGUES
77
2.4 BIOLOGICAL EVALUATION OF HYDRAZIDE-BASED ANALOGUES
85
2.5 CONCLUSIONS REGARDING HYDRAZIDE-BASED ANALOGUES
93
2.6 RATIONALE FOR PROPSOSED AMIDE-BASED ANALOGUES
95
2.7 SYNTHESIS OF AMIDE-BASED ANALOGUES
101
2.8 RESULTS AND DISCUSSION
115
2.9 CONCLUSIONS
159
Document Outline
- Distribution Agreement
- Signature sheet
- Abstractcoverpage
- thesisabstract_111609
- thesiscoverpage
- TABLE OF CONTENTs_111809 final
- List of Illustrations 111809 final
- List of Abbreviations
- Mosley Thesis Chapter 1_111709_b
- Mosley Thesis_Chapter 2_111709
- Mosley_Thesis_Chapter3_111809
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