Biomedical Engineering Reference
In-Depth Information
15
GABA and Glutamic Acid
Receptor Ligands
Bente Frølund and Ulf Madsen
CONTENTS
15.1 Introduction ....................................................................................................................... 239
15.2 Therapeutic Prospects for GABA and Glutamic Acid Neurotransmitter Systems ...........240
15.3 GABA Biosynthesis and Metabolism ............................................................................... 241
15.3.1 Inhibitors of GABA Metabolism......................................................................... 241
15.4 GABA Transport ............................................................................................................... 242
15.4.1 Inhibitors of GABA Transport ............................................................................ 242
15.5 GABA Receptors and Their Ligands................................................................................ 243
15.5.1 Ionotropic GABA Receptors ............................................................................... 243
15.5.2 Ionotropic GABA Receptor Ligands ...................................................................244
15.5.3 Modulatory Agents for the GABA
A
Receptor Complex .....................................246
15.5.4 GABA
B
Receptor Ligands................................................................................... 247
15.5.5 Ligands Differentiating the GABA
A
and GABA
C
Receptors.............................. 248
15.6 Glutamate—Neurotransmitter and Excitotoxin................................................................ 249
15.6.1 Receptor Classii cation and Uptake Mechanisms ............................................... 249
15.7 Ionotropic Glutamate Receptor Ligands ........................................................................... 250
15.7.1 NMDA Receptor Ligands.................................................................................... 250
15.7.2 Competitive NMDA Receptor Antagonists......................................................... 251
15.7.3 Uncompetitive and Noncompetitive NMDA Receptor Antagonists ................... 252
15.7.4 The Glycine Coagonist Site ................................................................................. 253
15.7.5 AMPA Receptor Agonists ................................................................................... 253
15.7.6 Competitive and Noncompetitive AMPA Receptor Antagonists ........................ 254
15.7.7 Modulatory Agents at AMPA Receptors............................................................. 255
15.7.8 KA Receptor Agonists and Antagonists.............................................................. 256
15.8 Metabotropic Glutamate Receptor Ligands ...................................................................... 257
15.8.1 Metabotropic Glutamate Receptor Agonists ....................................................... 257
15.8.2 Competitive Metabotropic Glutamate Receptor Antagonists ............................. 258
15.8.3 Allosteric Modulators of Metabotropic Glutamate Receptors ............................ 259
15.9 Design of Dimeric Positive AMPA Receptor Modulators ................................................ 260
15.10 Concluding Remarks......................................................................................................... 261
Further Readings............................................................................................................................ 262
15.1 INTRODUCTION
γ
-Aminobutyric acid (GABA [
15.1
]) and (
S
)-glutamic acid (Glu [
15.2
]) are the major inhibitory and
excitatory neurotransmitters, respectively, in the central nervous system (CNS) and form the basis
for neurotransmission in the mammalian CNS. Given the fact that the majority of central neurons
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