Drug Discovery for the Treatment of Addiction

Brian S. Fulton is a Visiting Lecturer in the Department of Chemistry and Chemical Biology at Northeastern University and has taught courses in organic chemistry, spectroscopy, and pharmaceutical sciences and has taught a one-semester course, Medicinal Chemistry of Psychiatric Drugs, at Harvard University Extension School. From 1987 – 2005, Dr. Fulton worked as an industrial organic chemist in the US and Europe. He obtained his B.S. in Chemistry at Missouri State University and his Ph.D. in Organic Chemistry at Iowa State University. He has written 17 peer-reviewed publications and given 8 presentations at scientific meetings.

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 Abuse and Addiction 16

2 Physiological Basis of Addiction—A Chemist's Interpretation 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 Addiction 22

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 Addiction 94

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-Brain Barrier 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 More Detailed Understanding of Addiction and the Central Nervous System 261

Appendix B Public Databases and Sources of Information of Interest 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