Drug Discovery for the Treatment of Addiction

Preface xiii
1 What Is Drug Addiction? 1
1.1 Definitions 2
1.2 The Drugs of Abuse 4
1.3 Schedule of Controlled Substances 5
1.4 Some Facts From 2012 NSDUH Study 6
1.5 The Addictive State 8
1.6 Theories of Addiction 12
1.7 Comorbidity 13
1.8 Genetic Aspects of Addiction 13
1.9 Approved Medications for the Treatment of Substance Abuseand Addiction 16
2 Physiological Basis of Addiction--A Chemist'sInterpretation 18
2.1 The Reward System 19
2.2 Neuroanatomy of the Reward System 21
2.3 Brief Review of the Central Nervous System and Addiction22
2.4 Neurotransmitters and Their Targets 25
2.5 Neurocircuitry and Neurotransmitters in Addiction 32
2.6 Location of Receptors 62
2.7 An Example 64
2.8 Use of Biological Markers 65
2.9 Memories and Addiction 68
2.10 Stress the HPA Axis and Addiction 72
3 Behavioral Pharmacology and Addiction 76
3.1 Animal Models of Addiction 76
3.2 Self-Administration 80
3.3 Conditioned Place Preference 85
3.4 Tolerance 86
3.5 Extinction/Withdrawal 87
3.6 Reinstatement (Animal Models of Relapse) 87
3.7 Drug Discrimination 89
3.8 Operant Sensation Seeking Model 92
3.9 Use of Animal Behavioral Models 92
Acknowledgments 93
4 Medication Development for the Treatment of Drug Addiction94
4.1 Lead Discovery 95
4.1.1 NIDA Addiction Treatment Discovery Program 96
4.2 Pharmacological Assays 103
4.3 Partial Agonist Approach 110
4.4 Allosteric Modulators 110
4.5 Functional Interactions Between Receptors 114
4.6 Multi-Target Drugs 121
4.7 Physicochemical Properties of CNS Drugs and Blood-BrainBarrier 124
4.8 Brain Imaging Agents 131
4.9 QT Prolongation 135
5 Medication Development for Narcotic Addiction 137
5.1 Pharmacology of Narcotic Addiction and Pain 138
5.2 Prescription Drug Addiction 139
5.3 Approved Medications 140
5.4 Medication Development 151
6 Medication Development for Stimulant Addiction 160
6.1 Pharmacology of Cocaine Addiction 160
6.2 Pharmacology of Methamphetamine Addiction 163
6.3 Medication Development 166
7 Medication Development for Depressant Addiction 213
7.1 Pharmacology of Alcohol Addiction 213
7.2 Approved Medications 214
7.3 Medication Development 219
7.4 Benzodiazepines 228
7.5 Barbiturates 229
8 Medication Development for Nicotine Addiction 230
8.1 Pharmacology of Nicotine Addiction 230
8.2 Approved Medications 232
8.3 Medication Development 237
9 Medication Development for Marijuana Addiction 240
9.1 Pharmacology of Marijuana Addiction 241
9.2 CB1 Antagonist: Rimonabant 243
9.3 Medication Development 244
10 Designer Drugs 252
10.1 Cathinone Drugs 253
10.2 MDMA--ECSTASY 256
10.3 Cannabinoid Designer Drugs 257
Conclusion 259
Appendix A Further Reading for Chemists Interested in a MoreDetailed Understanding of Addiction and the Central Nervous System261
Appendix B Public Databases and Sources of Information ofInterest to Medicinal Chemistry Addiction Researchers 262
Appendix C Glossary of Terms Used in Addiction Research 263
Appendix D Glossary of Terms Used in Medicinal Chemistry 271
References 290
Index 335