Pedro Merino, PhD, holds the Chair in Organic Chemistry at the University of Zaragoza, Spain. His scientific work has been presented in more than 220 papers, various book chapters, and one book. His research interests include chemical biology with particular focus on glycoscience, computational chemistry, asymmetric synthesis and catalysis.

• Preface xiPart I Neurotransmitter Systems 11 The Dopaminergic System 31.1 Introduction 31.2 Dopamine Receptors 51.2.1 Classification 51.2.2 Location 51.2.3 General Structural Considerations 61.2.4 Effector Mechanisms 81.2.5 Implication in Neurodisorders 91.2.6 D1]like Receptors 91.2.7 D2]like Receptors 121.3 Vesicular Monoamine Transporter (VMAT) 181.4 The Dopamine Transporter (DAT) 211.4.1 Structural Aspects 211.4.2 Molecular Mechanism 24References 262 The Noradrenergic System 412.1 Introduction 412.2 Adrenoreceptors 432.2.1 Classification 432.2.2 Location 442.2.3 General Structure Considerations 442.2.4 Effector Mechanisms 442.2.5 Implication in Neurodisorders 452.2.6 α1]Adrenoreceptors 462.2.7 α2]Adrenoreceptors 482.2.8 β]Adrenoreceptors 492.3 Neuropeptides Receptors 582.3.1 Neuropeptide Y Receptors 582.3.2 Galanin Receptors 612.4 Norepinephrine Transporter (NET) 63References 653 The Serotonergic System 813.1 Introduction 813.2 Serotonin Receptors 833.2.1 Classification 833.2.2 Location 863.2.3 General Structural Considerations 863.2.4 Effector Mechanism 873.2.5 Implication in Neurodisorders 883.2.6 5]HT1 Receptors 893.2.7 5]HT2 Receptors 923.2.8 5]HT3 Receptors 963.2.9 5]HT4 Receptors 983.2.10 5]HT5 Receptors 983.2.11 5]HT6 Receptors 1003.2.12 5]HT7 Receptors 1013.3 Serotonin Reuptake Transporter (SERT) 102References 1074 The Cholinergic System 1214.1 Introduction 1214.2 Cholinergic Receptors 1234.2.1 Classification 1234.2.2 Location 1244.2.3 Nicotinic Receptors 1254.2.3.1 Effector Mechanisms 1254.2.3.2 Implication in Neurodisorders 1264.2.3.3 Structure of Subunits 1264.2.3.4 Structure of Receptors 1264.2.4 Muscarinic Receptors 1324.2.4.1 Effector Mechanisms 1334.2.4.2 Implication in Neurodisorders 1344.2.4.3 M1 Receptor 1344.2.4.4 M2 Receptor 1354.2.4.5 M3 Receptor 1354.2.4.6 M4 Receptor 1394.2.4.7 M5 Receptor 1414.3 Cholinergic Transporters 1414.3.1 Vesicular Acetylcholine Transporter (VAChT) 1414.3.2 High]Affinity Choline Transporter (ChT) 143References 1455 The Glutamatergic System 1555.1 Introduction 1555.2 Glutamate Receptors 1575.2.1 Classification 1575.2.2 Ionotropic Receptors 1595.2.2.1 Location 1595.2.2.2 Effector Mechanisms 1615.2.2.3 Implication in Neurodisorders 1625.2.2.4 NMDA Receptors 1625.2.2.5 AMPA Receptors 1655.2.2.6 Kainate Receptors 1685.2.2.7 Delta Receptors 1725.2.3 Metabotropic Receptors 1735.2.3.1 Location 1735.2.3.2 Effector Mechanisms 1745.2.3.3 Implication in Neurodisorders 1755.2.3.4 Structural Features 1765.3 Glutamate Transporters 1845.3.1 Implication of Glutamate Transporters in Neurodegeneration 1865.3.2 Vesicular Glutamate Transporter 1 (VGLUT1) 1875.3.3 Vesicular Glutamate Transporter 2 (VGLUT2) 1875.3.4 Vesicular Glutamate Transporter 3 (VGLUT3) 187References 1886 The GABAergic System 1996.1 Introduction 1996.2 GABA Receptors 2016.2.1 Classification 2016.2.2 Location 2016.2.3 Implication in Neurodegenerative Disorders 2046.2.4 GABAA Receptors 2046.2.4.1 Effector Mechanisms 2056.2.4.2 Structure of Subunits 2066.2.5 GABAB Receptors 2106.2.5.1 Effector Mechanisms 2106.2.5.2 Structure of Receptors 2126.3 GABA Transporters 2136.3.1 Vesicular GABA Transporter (VGAT) 2166.3.2 Betaine Transporter (BGT1) 2166.3.3 Sodium] and Chloride]Dependent GABA Transporters (GAT1–3) 216References 218Part II Metabolism and Proteins 2277 Metabolism of Neurotransmitters 2297.1 Introduction 2297.2 Metabolism of Catecholamines 2297.2.1 Dopamine 2297.2.2 Norepinephrine (Noradrenaline) and Epinephrine (Adrenaline) 2347.3 Metabolism of Serotonin 2357.4 Metabolism of Acetylcholine 2387.5 Metabolism of Glutamic Acid and GABA 2397.5.1 Glutamic Acid 2397.5.2 γ]Aminobutyric Acid (GABA) 2407.5.3 Neurotransmission Mediated by Glutamic Acid and GABA Metabolisms 240References 2428 Enzymes Processing Neurotransmitters 2498.1 Tyrosine Hydroxylase (TH) 2498.2 Tryptophan Hydroxylase (Tryptophan]5]monoxygenase, TPH)) 2528.3 Aromatic Amino Acid Decarboxylase (AADC) 2558.4 Dopamine β]Hydroxylase (DBH) 2578.5 Monoamine Oxidase (MAO) 2598.6 Catecholamine]O]methyl Transferase (COMT) 2658.7 Phenylethanolamine]N]methyl Transferase (PNMT) 2708.8 5]Hydroxyindole]O]methyltransferase (HIOMT) 2728.9 Serotonin]N]acetyl Transferase (SNAT) 2748.10 Choline Acetyltransferase (ChAT) 2748.11 Acetylcholinesterase (AChE) 2768.12 Glutamic Acid Decarboxylase (GAD) 2808.13 Glutamine Synthetase (GLUL) 2818.14 GABA Transaminase (GABA]T) 284References 2869 Misfolded Proteins 3039.1 Introduction 3039.1.1 Amyloid β (Aβ) 3049.1.2 Tau (τ) 3079.1.3 α]Synuclein 313References 31610 Therapeutic Agents for Neurodegenerative Disorders 32510.1 Alzheimer’s Disease (AD) 32510.1.1 Acetylcholinesterase (AChE) Inhibitors 32510.1.2 Memantine (Namenda®) 33110.2 Parkinson’s Disease (PD) 33110.2.1 l]DOPA 33310.2.2 Dopaminergic Agonists 33510.2.3 MAO]B Inhibitors 34010.2.4 COMT Inhibitors 34310.2.5 Amantadine 34410.3 Lewy Body Disease (LBD) 34510.4 Huntington’s Disease (HD) 34610.5 Friedreich’s Ataxia (FA) 34610.6 Amyotrophic Lateral Sclerosis (ALS) 34610.7 Spinal Muscular Atrophy (SMA) 347References 347Index 359

Pedro Merino, PhD, holds the Chair in Organic Chemistry at the University of Zaragoza, Spain. His scientific work has been presented in more than 220 papers, various book chapters, and one book. His research interests include chemical biology with particular focus on glycoscience, computational chemistry, asymmetric synthesis and catalysis.

• Preface xiPart I Neurotransmitter Systems 11 The Dopaminergic System 31.1 Introduction 31.2 Dopamine Receptors 51.2.1 Classification 51.2.2 Location 51.2.3 General Structural Considerations 61.2.4 Effector Mechanisms 81.2.5 Implication in Neurodisorders 91.2.6 D1]like Receptors 91.2.7 D2]like Receptors 121.3 Vesicular Monoamine Transporter (VMAT) 181.4 The Dopamine Transporter (DAT) 211.4.1 Structural Aspects 211.4.2 Molecular Mechanism 24References 262 The Noradrenergic System 412.1 Introduction 412.2 Adrenoreceptors 432.2.1 Classification 432.2.2 Location 442.2.3 General Structure Considerations 442.2.4 Effector Mechanisms 442.2.5 Implication in Neurodisorders 452.2.6 α1]Adrenoreceptors 462.2.7 α2]Adrenoreceptors 482.2.8 β]Adrenoreceptors 492.3 Neuropeptides Receptors 582.3.1 Neuropeptide Y Receptors 582.3.2 Galanin Receptors 612.4 Norepinephrine Transporter (NET) 63References 653 The Serotonergic System 813.1 Introduction 813.2 Serotonin Receptors 833.2.1 Classification 833.2.2 Location 863.2.3 General Structural Considerations 863.2.4 Effector Mechanism 873.2.5 Implication in Neurodisorders 883.2.6 5]HT1 Receptors 893.2.7 5]HT2 Receptors 923.2.8 5]HT3 Receptors 963.2.9 5]HT4 Receptors 983.2.10 5]HT5 Receptors 983.2.11 5]HT6 Receptors 1003.2.12 5]HT7 Receptors 1013.3 Serotonin Reuptake Transporter (SERT) 102References 1074 The Cholinergic System 1214.1 Introduction 1214.2 Cholinergic Receptors 1234.2.1 Classification 1234.2.2 Location 1244.2.3 Nicotinic Receptors 1254.2.3.1 Effector Mechanisms 1254.2.3.2 Implication in Neurodisorders 1264.2.3.3 Structure of Subunits 1264.2.3.4 Structure of Receptors 1264.2.4 Muscarinic Receptors 1324.2.4.1 Effector Mechanisms 1334.2.4.2 Implication in Neurodisorders 1344.2.4.3 M1 Receptor 1344.2.4.4 M2 Receptor 1354.2.4.5 M3 Receptor 1354.2.4.6 M4 Receptor 1394.2.4.7 M5 Receptor 1414.3 Cholinergic Transporters 1414.3.1 Vesicular Acetylcholine Transporter (VAChT) 1414.3.2 High]Affinity Choline Transporter (ChT) 143References 1455 The Glutamatergic System 1555.1 Introduction 1555.2 Glutamate Receptors 1575.2.1 Classification 1575.2.2 Ionotropic Receptors 1595.2.2.1 Location 1595.2.2.2 Effector Mechanisms 1615.2.2.3 Implication in Neurodisorders 1625.2.2.4 NMDA Receptors 1625.2.2.5 AMPA Receptors 1655.2.2.6 Kainate Receptors 1685.2.2.7 Delta Receptors 1725.2.3 Metabotropic Receptors 1735.2.3.1 Location 1735.2.3.2 Effector Mechanisms 1745.2.3.3 Implication in Neurodisorders 1755.2.3.4 Structural Features 1765.3 Glutamate Transporters 1845.3.1 Implication of Glutamate Transporters in Neurodegeneration 1865.3.2 Vesicular Glutamate Transporter 1 (VGLUT1) 1875.3.3 Vesicular Glutamate Transporter 2 (VGLUT2) 1875.3.4 Vesicular Glutamate Transporter 3 (VGLUT3) 187References 1886 The GABAergic System 1996.1 Introduction 1996.2 GABA Receptors 2016.2.1 Classification 2016.2.2 Location 2016.2.3 Implication in Neurodegenerative Disorders 2046.2.4 GABAA Receptors 2046.2.4.1 Effector Mechanisms 2056.2.4.2 Structure of Subunits 2066.2.5 GABAB Receptors 2106.2.5.1 Effector Mechanisms 2106.2.5.2 Structure of Receptors 2126.3 GABA Transporters 2136.3.1 Vesicular GABA Transporter (VGAT) 2166.3.2 Betaine Transporter (BGT1) 2166.3.3 Sodium] and Chloride]Dependent GABA Transporters (GAT1–3) 216References 218Part II Metabolism and Proteins 2277 Metabolism of Neurotransmitters 2297.1 Introduction 2297.2 Metabolism of Catecholamines 2297.2.1 Dopamine 2297.2.2 Norepinephrine (Noradrenaline) and Epinephrine (Adrenaline) 2347.3 Metabolism of Serotonin 2357.4 Metabolism of Acetylcholine 2387.5 Metabolism of Glutamic Acid and GABA 2397.5.1 Glutamic Acid 2397.5.2 γ]Aminobutyric Acid (GABA) 2407.5.3 Neurotransmission Mediated by Glutamic Acid and GABA Metabolisms 240References 2428 Enzymes Processing Neurotransmitters 2498.1 Tyrosine Hydroxylase (TH) 2498.2 Tryptophan Hydroxylase (Tryptophan]5]monoxygenase, TPH)) 2528.3 Aromatic Amino Acid Decarboxylase (AADC) 2558.4 Dopamine β]Hydroxylase (DBH) 2578.5 Monoamine Oxidase (MAO) 2598.6 Catecholamine]O]methyl Transferase (COMT) 2658.7 Phenylethanolamine]N]methyl Transferase (PNMT) 2708.8 5]Hydroxyindole]O]methyltransferase (HIOMT) 2728.9 Serotonin]N]acetyl Transferase (SNAT) 2748.10 Choline Acetyltransferase (ChAT) 2748.11 Acetylcholinesterase (AChE) 2768.12 Glutamic Acid Decarboxylase (GAD) 2808.13 Glutamine Synthetase (GLUL) 2818.14 GABA Transaminase (GABA]T) 284References 2869 Misfolded Proteins 3039.1 Introduction 3039.1.1 Amyloid β (Aβ) 3049.1.2 Tau (τ) 3079.1.3 α]Synuclein 313References 31610 Therapeutic Agents for Neurodegenerative Disorders 32510.1 Alzheimer’s Disease (AD) 32510.1.1 Acetylcholinesterase (AChE) Inhibitors 32510.1.2 Memantine (Namenda®) 33110.2 Parkinson’s Disease (PD) 33110.2.1 l]DOPA 33310.2.2 Dopaminergic Agonists 33510.2.3 MAO]B Inhibitors 34010.2.4 COMT Inhibitors 34310.2.5 Amantadine 34410.3 Lewy Body Disease (LBD) 34510.4 Huntington’s Disease (HD) 34610.5 Friedreich’s Ataxia (FA) 34610.6 Amyotrophic Lateral Sclerosis (ALS) 34610.7 Spinal Muscular Atrophy (SMA) 347References 347Index 359

Pedro Merino, PhD, holds the Chair in Organic Chemistry at the University of Zaragoza, Spain. His scientific work has been presented in more than 220 papers, various book chapters, and one book. His research interests include chemical biology with particular focus on glycoscience, computational chemistry, asymmetric synthesis and catalysis.

• Preface xiPart I Neurotransmitter Systems 11 The Dopaminergic System 31.1 Introduction 31.2 Dopamine Receptors 51.2.1 Classification 51.2.2 Location 51.2.3 General Structural Considerations 61.2.4 Effector Mechanisms 81.2.5 Implication in Neurodisorders 91.2.6 D1]like Receptors 91.2.7 D2]like Receptors 121.3 Vesicular Monoamine Transporter (VMAT) 181.4 The Dopamine Transporter (DAT) 211.4.1 Structural Aspects 211.4.2 Molecular Mechanism 24References 262 The Noradrenergic System 412.1 Introduction 412.2 Adrenoreceptors 432.2.1 Classification 432.2.2 Location 442.2.3 General Structure Considerations 442.2.4 Effector Mechanisms 442.2.5 Implication in Neurodisorders 452.2.6 α1]Adrenoreceptors 462.2.7 α2]Adrenoreceptors 482.2.8 β]Adrenoreceptors 492.3 Neuropeptides Receptors 582.3.1 Neuropeptide Y Receptors 582.3.2 Galanin Receptors 612.4 Norepinephrine Transporter (NET) 63References 653 The Serotonergic System 813.1 Introduction 813.2 Serotonin Receptors 833.2.1 Classification 833.2.2 Location 863.2.3 General Structural Considerations 863.2.4 Effector Mechanism 873.2.5 Implication in Neurodisorders 883.2.6 5]HT1 Receptors 893.2.7 5]HT2 Receptors 923.2.8 5]HT3 Receptors 963.2.9 5]HT4 Receptors 983.2.10 5]HT5 Receptors 983.2.11 5]HT6 Receptors 1003.2.12 5]HT7 Receptors 1013.3 Serotonin Reuptake Transporter (SERT) 102References 1074 The Cholinergic System 1214.1 Introduction 1214.2 Cholinergic Receptors 1234.2.1 Classification 1234.2.2 Location 1244.2.3 Nicotinic Receptors 1254.2.3.1 Effector Mechanisms 1254.2.3.2 Implication in Neurodisorders 1264.2.3.3 Structure of Subunits 1264.2.3.4 Structure of Receptors 1264.2.4 Muscarinic Receptors 1324.2.4.1 Effector Mechanisms 1334.2.4.2 Implication in Neurodisorders 1344.2.4.3 M1 Receptor 1344.2.4.4 M2 Receptor 1354.2.4.5 M3 Receptor 1354.2.4.6 M4 Receptor 1394.2.4.7 M5 Receptor 1414.3 Cholinergic Transporters 1414.3.1 Vesicular Acetylcholine Transporter (VAChT) 1414.3.2 High]Affinity Choline Transporter (ChT) 143References 1455 The Glutamatergic System 1555.1 Introduction 1555.2 Glutamate Receptors 1575.2.1 Classification 1575.2.2 Ionotropic Receptors 1595.2.2.1 Location 1595.2.2.2 Effector Mechanisms 1615.2.2.3 Implication in Neurodisorders 1625.2.2.4 NMDA Receptors 1625.2.2.5 AMPA Receptors 1655.2.2.6 Kainate Receptors 1685.2.2.7 Delta Receptors 1725.2.3 Metabotropic Receptors 1735.2.3.1 Location 1735.2.3.2 Effector Mechanisms 1745.2.3.3 Implication in Neurodisorders 1755.2.3.4 Structural Features 1765.3 Glutamate Transporters 1845.3.1 Implication of Glutamate Transporters in Neurodegeneration 1865.3.2 Vesicular Glutamate Transporter 1 (VGLUT1) 1875.3.3 Vesicular Glutamate Transporter 2 (VGLUT2) 1875.3.4 Vesicular Glutamate Transporter 3 (VGLUT3) 187References 1886 The GABAergic System 1996.1 Introduction 1996.2 GABA Receptors 2016.2.1 Classification 2016.2.2 Location 2016.2.3 Implication in Neurodegenerative Disorders 2046.2.4 GABAA Receptors 2046.2.4.1 Effector Mechanisms 2056.2.4.2 Structure of Subunits 2066.2.5 GABAB Receptors 2106.2.5.1 Effector Mechanisms 2106.2.5.2 Structure of Receptors 2126.3 GABA Transporters 2136.3.1 Vesicular GABA Transporter (VGAT) 2166.3.2 Betaine Transporter (BGT1) 2166.3.3 Sodium] and Chloride]Dependent GABA Transporters (GAT1–3) 216References 218Part II Metabolism and Proteins 2277 Metabolism of Neurotransmitters 2297.1 Introduction 2297.2 Metabolism of Catecholamines 2297.2.1 Dopamine 2297.2.2 Norepinephrine (Noradrenaline) and Epinephrine (Adrenaline) 2347.3 Metabolism of Serotonin 2357.4 Metabolism of Acetylcholine 2387.5 Metabolism of Glutamic Acid and GABA 2397.5.1 Glutamic Acid 2397.5.2 γ]Aminobutyric Acid (GABA) 2407.5.3 Neurotransmission Mediated by Glutamic Acid and GABA Metabolisms 240References 2428 Enzymes Processing Neurotransmitters 2498.1 Tyrosine Hydroxylase (TH) 2498.2 Tryptophan Hydroxylase (Tryptophan]5]monoxygenase, TPH)) 2528.3 Aromatic Amino Acid Decarboxylase (AADC) 2558.4 Dopamine β]Hydroxylase (DBH) 2578.5 Monoamine Oxidase (MAO) 2598.6 Catecholamine]O]methyl Transferase (COMT) 2658.7 Phenylethanolamine]N]methyl Transferase (PNMT) 2708.8 5]Hydroxyindole]O]methyltransferase (HIOMT) 2728.9 Serotonin]N]acetyl Transferase (SNAT) 2748.10 Choline Acetyltransferase (ChAT) 2748.11 Acetylcholinesterase (AChE) 2768.12 Glutamic Acid Decarboxylase (GAD) 2808.13 Glutamine Synthetase (GLUL) 2818.14 GABA Transaminase (GABA]T) 284References 2869 Misfolded Proteins 3039.1 Introduction 3039.1.1 Amyloid β (Aβ) 3049.1.2 Tau (τ) 3079.1.3 α]Synuclein 313References 31610 Therapeutic Agents for Neurodegenerative Disorders 32510.1 Alzheimer’s Disease (AD) 32510.1.1 Acetylcholinesterase (AChE) Inhibitors 32510.1.2 Memantine (Namenda®) 33110.2 Parkinson’s Disease (PD) 33110.2.1 l]DOPA 33310.2.2 Dopaminergic Agonists 33510.2.3 MAO]B Inhibitors 34010.2.4 COMT Inhibitors 34310.2.5 Amantadine 34410.3 Lewy Body Disease (LBD) 34510.4 Huntington’s Disease (HD) 34610.5 Friedreich’s Ataxia (FA) 34610.6 Amyotrophic Lateral Sclerosis (ALS) 34610.7 Spinal Muscular Atrophy (SMA) 347References 347Index 359