Bente Frelund 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 GABAa Receptor Complex 246

15.5.4 GABAB Receptor Ligands 247

15.5.5 Ligands Differentiating the GABAA and GABAC Receptors 248

15.6 Glutamate—Neurotransmitter and Excitotoxin 249

15.6.1 Receptor Classification 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

y-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

Presynaptic terminal

Presynaptic terminal nh2

HOOC COOH

HOOC COOH

Neuronal uptake

Glial cell Gln/aKG SSA

Glial uptake

Neuronal uptake

Presynaptic terminal

Glial cell Gln/aKG SSA

Glial uptake

Neuronal uptake

FIGURE 15.1 Schematic illustration of the biochemical pathways, transport mechanisms, and receptors at Glu and GABA operated neurons. Enzymes are indicated by the following: a, glutaminase; b, glutamine synthase; c, aspartate synthase; d, L-glutamic acid decarboxylase (GAD); e, GABA aminotransferase (GABA-AT).

Neuronal uptake

Postsynaptic terminals

FIGURE 15.1 Schematic illustration of the biochemical pathways, transport mechanisms, and receptors at Glu and GABA operated neurons. Enzymes are indicated by the following: a, glutaminase; b, glutamine synthase; c, aspartate synthase; d, L-glutamic acid decarboxylase (GAD); e, GABA aminotransferase (GABA-AT).

are under excitatory and inhibitory controls by Glu and GABA, the balance between the activities of the two is of utmost importance for CNS functions. Both neurotransmitter systems are involved in the regulation of a variety of physiological mechanisms and dysfunctions of either of the two can be related to various neurological disorders in the CNS.

The transmission processes mediated by Glu and GABA are very complex and highly regulated. A general and simple model for the Glu and GABA neurotransmissions is shown in Figure 15.1. Glu and GABA are formed in their respective presynaptic nerve terminals and upon depolarization released into the synaptic cleft in a high concentration to activate postsynaptic ionotropic receptors that directly modify the membrane potential of the receptive neuron, generating an excitatory or inhibitory postsynaptic potential. This basic system is further modulated through G-protein-coupled receptors for a variety of neuroactive substances including Glu and GABA themselves. Subsequently Glu and GABA are removed from the synaptic cleft into surrounding neurons and glia cells via specialized transporters to restore the neurotransmitter balance. The reuptaken Glu and GABA are enzymatically metabolized to form glutamine (Gln) or a-ketoglutarate (aKG) and succinic acid semialdehyde (SSA), respectively.

15.2 THERAPEUTIC PROSPECTS FOR GABA AND GLUTAMIC ACID NEUROTRANSMITTER SYSTEMS

The therapeutic potentials of manipulating these neurotransmitter systems seem to be unlimited. Therefore, virtually all of the known molecular components of the GABA and Glu neurotrans-mitter systems have been considered as potential therapeutic targets. The therapeutic indications are numerous and include neurodegenerative disorders, e.g., Alzheimer's disease, Parkinson's disease, Huntington's chorea, epilepsy and stroke, and other neurologic disorders, e.g., schizophrenia, depression, anxiety, and pain. Furthermore narcolepsy, spasticity, muscle relaxation, and insomnia are among the vast number of therapeutic possibilities and finally cognitive enhancers can be mentioned as a much pursued therapeutic application.

GABA-based therapeutics have been in clinical use for some time, where the most successful therapeutic application to date involve the upregulation of GABA activity by the modulation of the ionotropic GABAa receptor, notably by benzodiazepines (BZD) and barbiturates. Vigabatrin (15.3)

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