Design, Synthesis, and Biological Evaluation of Subunit-Selective N-Methyl-D-Aspartate Receptor Antagonists Pubblico

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

About this Dissertation

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• 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	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic Chemistry, Pharmaceutical
Parola chiave	NR2B NMDA receptor NR2D N-Methyl-D-Aspartate hERG
Committee Chair / Thesis Advisor	Liotta, Dennis C, Emory University
Committee Members	Menger, Fred M, Emory University McDonald, Frank, Emory University

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