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Herausgeber: John Wiley & Sons
Kategorie: Wissenschaft und neue Technologien
Sprache: Englisch

Beschreibung

With addiction a key target for drug discovery efforts, this book fills an important and timely need for medicinal chemists who need to understand complex neuroscience issues. The author illustrates medicinal chemistry's prominent role in treating addiction and covers specific drugs of abuse including narcotics, stimulants, depressants, nicotine, and marijuana. * Interprets complex neuro- biological and pharmacological information, like the drug-reward system, for medicinal chemists * Emphasizes neurotransmitters and neurochemical mechanisms of addictive drugs * Pulls together information on the many potential drug targets for treating addiction * Stresses unique medicinal chemistry problems when describing pharmacology testing methods and drug development

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Leseprobe

DRUG DISCOVERY FOR THE TREATMENT OF ADDICTION

Medicinal Chemistry Strategies

BRIAN S. FULTON

Visiting Lecturer Department of Chemistry and Chemical Biology Northeastern University

Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permissions.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

Fulton, Brian S., author. Drug discovery for the treatment of addiction : medicinal chemistry strategies / Brian S. Fulton. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-61416-7 (cloth) I. Title. [DNLM: 1. Substance-Related Disorders–drug therapy. 2. Drug Discovery. 3. Neurotransmitter Agents. WM 270] RM301.25 615.1′9–dc23

2014012670

For those who want, but can’t.

Preface

1 What Is Drug Addiction?

1.1 Definitions

1.2 The Drugs of Abuse

1.3 Schedule of Controlled Substances

1.4 Some Facts From 2012 NSDUH Study

1.5 The Addictive State

1.6 Theories of Addiction

1.7 Comorbidity

1.8 Genetic Aspects of Addiction

1.9 Approved Medications for the Treatment of Substance Abuse and Addiction

2 Physiological Basis of Addiction—A Chemist'S Interpretation

2.1 The Reward System

2.2 Neuroanatomy of the Reward System

2.3 Brief Review of the Central Nervous System and Addiction

2.4 Neurotransmitters and Their Targets

2.5 Neurocircuitry and Neurotransmitters in Addiction

2.6 Location of Receptors

2.7 An Example

2.8 Use of Biological Markers

2.9 Memories and Addiction

2.10 Stress, the HPA Axis, and Addiction

Notes

3 Behavioral Pharmacology and Addiction

3.1 Animal Models of Addiction

3.2 Self-Administration

3.3 Conditioned Place Preference

3.4 Tolerance

3.5 Extinction/Withdrawal

3.6 Reinstatement (Animal Models of Relapse)

3.7 Drug Discrimination

3.8 Operant Sensation Seeking Model

3.9 Use of Animal Behavioral Models

Acknowledgments

Notes

4 Medication Development for the Treatment of Drug Addiction

4.1 Lead Discovery

4.2 Pharmacological Assays

4.3 Partial Agonist Approach

4.4 Allosteric Modulators

4.5 Functional Interactions Between Receptors

4.6 Multi-Target Drugs

4.7 Physicochemical Properties of CNS Drugs and Blood-Brain Barrier

4.8 Brain Imaging Agents

4.9 QT Prolongation

Notes

5 Medication Development for Narcotic Addiction

5.1 Pharmacology of Narcotic Addiction and Pain

5.2 Prescription Drug Addiction

5.3 Approved Medications

5.4 Medication Development

6 Medication Development for Stimulant Addiction

6.1 Pharmacology of Cocaine Addiction

6.2 Pharmacology of Methamphetamine Addiction

6.3 Medication Development

7 Medication Development for Depressant Addiction

7.1 Pharmacology of Alcohol Addiction

7.2 Approved Medications

7.3 Medication Development

7.4 Benzodiazepines

7.5 Barbiturates

8 Medication Development for Nicotine Addiction

8.1 Pharmacology of Nicotine Addiction

8.2 Approved Medications

8.3 Medication Development

9 Medication Development for Marijuana Addiction

9.1 Pharmacology of Marijuana Addiction

9.2 CB

Antagonist: Rimonabant

9.3 Medication Development

10 Designer Drugs

10.1 Cathinone Drugs

10.2 MDMA—ECSTASY

10.3 Cannabinoid Designer Drugs

Conclusion

Appendix A Further Reading for Chemists Interested in a More Detailed Understanding of Addiction and the Central Nervous System

Appendix B Public Databases and Sources of Information of Interest to Medicinal Chemistry Addiction Researchers

Appendix C Glossary of Terms Used in Addiction Research

Appendix D Glossary of Terms Used in Medicinal Chemistry

References

Index

End User License Agreement

List of Tables

Chapter 2

Table 2.1

Table 2.2

Chapter 3

Table 3.1

Chapter 4

Table 4.1

Table 4.2

Chapter 6

Table 6.1

List of Illustrations

Chapter 1

Figure 1.1

Structures of the most common drugs of abuse

Chapter 2

Figure 2.1

Modern operant conditioning chamber (skinner box) (Reprinted with permission from Thomsen and Caine.

168

Figure 2.2

Addiction circuitry schematic. Abbreviations: AMG, amygdala; LC, locus ceruleus; Hipp, hippocampus; NAc, nucleus accumbens; RN, raphe nuclei; VTA, ventral tegmental area

Figure 2.3

Addiction circuit

Figure 2.4

Depiction of a synapse

Figure 2.5

Structures of neurotransmitters

Figure 2.6

Formation of cAMP from ATP

Figure 2.7

Function of PLC

Figure 2.8

Inhibition of inositol monophosphate phosphatase by lithium

Figure 2.9

Glutaminergic system in drug addiction

Figure 2.10

Crystal structures of the mGluR1 receptor (Adapted with permission from Kunishima et al.

Figure 2.11

Glutaminergic synapse during addiction

Figure 2.12

GABAergic circuitry in addiction

Figure 2.13

GABAergic synapse during addiction

Figure 2.14

Cholinergic circuitry in addiction

Figure 2.15

Structure of M

receptor. (a) M

receptor in profile bound to the antagonist QNB. (b) Cytoplasmic surface showing conserved DRY (aspartic acid:arginine:tyrosine) residues in TM3. (c) Extracellular view into QNB binding pocket. (d) Extracellular view with solvent-accessible surface rendering shows a funnel-shaped vestibule and a nearly buried QNB binding pocket. (e) An aqueous channel depicted as a solvent accessible surface model (green in color figure), extending from the extracellular surface into the transmembrane core, is interrupted by a layer of three hydrophobic residues (blue spheres in color figure) located at isoleucine I392 and leucine L114. Well-ordered water molecules are shown as red dots (Reprinted with permission from Haga et al.

Figure 2.16

receptor complexed with allosteric and orthosteric ligands. (a) The M

receptor occupied by the orthosteric agonist iperoxo was crystallized in complex with the positive allosteric modulator LY2119620. (b) The allosteric ligand binds to the extracellular vestibule just above the orthosteric agonist. A cross section through the membrane plane shows the relative positions of the two ligands with the positive allosteric modulator LY2119620 binding above the orthosteric agonist iperoxo. (c) Several polar contacts are involved in LY2119620 binding, in addition to extensive aromatic stacking interactions with Trp422

7.35

and Tyr177

ECL2

. (d) Upon activation, the M

receptor undergoes substantial conformational changes in the extracellular surface, leading to a contraction of the extracellular vestibule. In particular, as depicted by the arrows, ECL3, TM6, and TM5 undergo a significant contraction. (e) This creates a binding site that fits tightly around the allosteric modulator, which would otherwise be unable to interact extensively with the extracellular vestibule in the inactive receptor conformation (Reprinted with permission from Kruse et al.

Figure 2.17

Dopaminergic circuitry in addiction

Figure 2.18

Molecular interactions in tolerance

Figure 2.19

Adrenergic circuitry in addiction

Figure 2.20

Serotonergic circuitry in addiction

Figure 2.21

Structures of 5-HT ligands

Figure 2.22

Structures of VMAT2 ligands

Figure 2.23

Structures of endogenous cannabinoids

Figure 2.24

Structures of opioid ligands

Figure 2.25

Synthesis of [

H]-BMS-725519

Figure 2.26

Location of receptors in the reward system

Figure 2.27

Receptor-level action of reinforcing drugs in the ventral tegmental area (Reprinted with permission from Zachariou et al.

Figure 2.28

How reconsolidation is studied (Reprinted with permission from Tronson and Taylor.

683

Figure 2.29

HPA axis

Chapter 3

Figure 3.1

Operant chamber for self-administration (Reprinted with permission from Thomsen and Caine.

168

Figure 3.2

Dose-effect curve for cocaine self-administration under a fixed ratio 5. Abscissa: dose of self-administered cocaine per injection, log scale except for zero dose. Ordinate: rate of self-administration expressed as injections per hour (Reprinted with permission from Thomsen and Caine.

168

Figure 3.3

Structure of the conditioned preference place paradigm (Reprinted with permission from Wang et al.

170

Figure 3.4

Experimental paradigm for reinstatement of drug-seeking behavior (Reprinted with permission from Yahyavi-Firouz-Abadi and See.

171

Figure 3.5

Effects of cocaine, D-amphetamine, and the κ-agonist U-50488 in mice trained to discriminate cocaine from saline. Abscissa: drug dose in mg/kg; “V” indicates vehicle. Ordinates: percentage cocaine-appropriate responses (top), response rate in responses per second (bottom) (Reprinted with permission from Thomsen et al.

177

Chapter 4

Figure 4.1

Prototypical saturation binding curves

Figure 4.2

Plot of competition-binding experiment. NS, nonspecific binding (Reprinted with permission from Motulsky and Neubig.

684

Figure 4.3

Competitive binding curve (Reprinted with permission from Motulsky and Neubig.

684

Figure 4.4

Structural topology and ligands of typical orthosteric and allosteric sites of 7TM receptors (Adapted with permission from Melancon et al.

239

Figure 4.5

Functional assays, measuring calcium fluorescence as a surrogate for 7TMR receptor activation, employed to identify and profile 7TMR allosteric modulators (Adapted with permission from Melancon et al.

239

Figure 4.6

Morphine THC synergism (Reprinted with permission from Smith et al.

685

Figure 4.7

and μ-opioid agonists

Figure 4.8

Ligands used for MDAN series

Figure 4.9

Structure of NOP bivalent antagonist

Figure 4.10

Solution versus liposome conformations of NOP bivalent ligand (Reprinted with permission from Borioni et al.

271

Figure 4.11

Diagram of transport mechanism through BBB (Reprinted with permission from Mehdipour and Hamidi.

280

Figure 4.12

Feynman diagram for the electron-positron annihilation reaction

Figure 4.13

Synthesis of [

C]-raclopride

Figure 4.14

Opioid PET ligands

Figure 4.15

Synthesis of radiolabeled LY2795050

Figure 4.16

Structure of

C-GR103545

Chapter 5

Figure 5.1

Structures of common opioids

Figure 5.2

Synthesis of methadone

Figure 5.3

SAR of methadone

Figure 5.4

Active metabolites of LAAM

Figure 5.5

Synthesis of buprenorphine

Figure 5.6

Structures of common opioid antagonists

Figure 5.7

Synthesis of naltrexone

Figure 5.8

Structures and binding affinities of clonidine and lofexidine

Figure 5.9

Synthesis of clonidine

Figure 5.10

Synthesis of (S)-(−)-lofexidine

Figure 5.11

Synthesis of (R)-(+)-lofexidine

Figure 5.12

SAR of α

-agonists/α

-antagonists

Figure 5.13

Synthesis of tramadol

Figure 5.14

Structures of tramadol stereoisomers

Figure 5.15

Diastereoselective synthesis of

trans

-tramadol

Figure 5.16

Diastereoselective synthesis of

cis

-tramadol

Figure 5.17

Binding of memantine to NMDA

Figure 5.18

Synthesis of memantine

Figure 5.19

FAAH and MAGL inhibitors

Figure 5.20

Optimization of FAAH inhibitor PF-3845

Figure 5.21

Synthesis of ondansetron

Figure 5.22

Structures of ibogaine and 18-MC

Chapter 6

Figure 6.1

Synthesis of ibudilast

Figure 6.2

SAR of ibudilast

Figure 6.3

Structures of vigabatrin and CPP-115

Figure 6.4

Synthesis of CPP-115

Figure 6.5

Synthesis of azabicycloheptanedione

Figure 6.6

Synthesis of nepicastat

Figure 6.7

Oxidation of dopamine by aldehyde dehydrogenase 2: CVT-10216

Figure 6.8

Structure of CVT-10216

Figure 6.9

Development of M

selective ligands

Figure 6.10

SAR of M

agonists (Adapted with permission from Lebois et al.

421

Figure 6.11

Synthesis of Xanomeline

Figure 6.12

Xanomeline from arecoline

Figure 6.13

Constrained glutamic acid mGlu

2/3

PAMs

Figure 6.14

Synthesis of LY354740

Figure 6.15

Conversion of CMG to CMGDE

Figure 6.16

Synthesis of [

C]-CMGDE

Figure 6.17

Discovery of BINA

Figure 6.18

Heterocyclic BINA analog

Figure 6.19

Representative mGlu

PAMs

Figure 6.20

Synthesis of fenobam

Figure 6.21

Tautomers of fenobam

Figure 6.22

Solid-state structure of fenobam

Figure 6.23

Structure and binding affinities of MPEP

Figure 6.24

Synthesis of MTEP

Figure 6.25

SAR study of MTEP

Figure 6.26

Benzothiazole mGlu

NAM

Figure 6.27

Structure of AMN082

Figure 6.28

Formation of cystine from cysteine

Figure 6.29

Selective D

ligands

Figure 6.30

Structure and binding profile of aripiprazole

Figure 6.31

Structure of a D

partial agonist/D

antagonist

Figure 6.32

Structures of DAT reuptake inhibitors GBR12909 and benztropine

Figure 6.33

Binding affinities of DAT/σ rimcazole ligands (

, nM)

Figure 6.34

Synthesis of SA4503

Figure 6.35

Synthesis of mirtazapine

Figure 6.36

Conversion of mianserin to mirtazapine

Figure 6.37

Structures of 5-HT

antagonist M100907 and 5-HT

agonist WAY163909

Figure 6.38

Synthesis of buspirone

Figure 6.39

Synthesis of modafinil

Figure 6.40

Enantiomers of modafinil

Figure 6.41

Synthesis of lobeline analogs

Figure 6.42

Synthesis of tiagabine

Figure 6.43

Baclofen

Figure 6.44

Construction of propranolol

Figure 6.45

Synthesis of CP-154,526

Chapter 7

Figure 7.1

Enzymatic reduction in disulfiram

Figure 7.2

Synthesis of disulfiram

Figure 7.3

Structures of acamprosate and GABA analogs

Figure 7.4

Synthesis of acamprosate

Figure 7.5

Binding of naltrexone in human brain. Mean images of the distribution of μ-opioid receptors in the brain of 21 alcoholics after IV administration of [

C]-carfentanil during scans conducted pre-naltrexone treatment (top panel) and during naltrexone treatment (bottom panel). Images in e-book edition are color-coded according to the scale shown (0–1.5) so that highest concentrations of the radiotracer are represented by red and lowest concentrations by black/purple (Reprinted with permission from Weerts et al.

567

Figure 7.6

Synthesis of nalmefene from naltrexone

Figure 7.7

Structure and opioid binding affinities of 6-β-naltrexol

Figure 7.8

SAR of naltrexamine amides

Figure 7.9

Synthesis and opioid binding affinities of ALKS 33

Figure 7.10

Synthesis of topiramate

Figure 7.11

Structures of CRF

antagonists

Figure 7.12

SAR development for NBI-77860/GSK561679

Figure 7.13

Structure of LY686017

Figure 7.14

Synthesis of pioglitazone

Chapter 8

Figure 8.1

Theoretical representation of the differences in functional efficacy of a full agonist (nicotine) and a weak or potent partial agonist, alone and combined with nicotine. (a) Partial agonists have a smaller maximal effect than does the agonist nicotine (i.e., increasing their concentration or exposure does not further increase their effect). When not smoking, the partial agonist has a mild nicotine-like effect and can relieve craving and withdrawal, dependent on the relative functional efficacy versus nicotine, the receptor-binding affinity, and free levels in the brain. (b) To exert an antagonist effect (i.e., to block the reinforcing effect of nicotine when smoking), a partial agonist should have high binding affinity and sufficiently free levels in the brain (

eff

) to inhibit the effect of nicotine completely, resulting in the same maximal effect as the partial agonist alone. Partial agonists with poor binding affinity and/or low brain penetration have insufficient

eff

to be efficacious as an antagonist

in vivo

(Reprinted with permission from Rollema et al.

605

Figure 8.2

Structural similarities of morphine and cytisine

Figure 8.3

Development of varenicline from cytosine

Figure 8.4

Enantiomeric forms of bupropion

Figure 8.5

Hydroxyl metabolites of bupropion

Figure 8.6

Synthesis of bupropion

Figure 8.7

Synthesis of GSK598809

Chapter 9

Figure 9.1

Synthesis of rimonabant

Figure 9.2

Synthesis of nabilone

Figure 9.3

Mechanism of cyclization

Figure 9.4

Structure of cannabidiol

Figure 9.5

Synthesis of gabapentin

Figure 9.6

Structure of PF-04457845

Chapter 10

Figure 10.1

Structures of abused phenethylamines

Guide

Cover

Table of Contents

Preface

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PREFACE

This book arose from a review article I wrote in 2008 for Annual Reports in Medicinal Chemistry. Following publication, Jonathan Rose of Wiley and Sons contacted me to see if I would be interested in writing a book on the subject. Sure, I thought, how hard can that be? That will take only of couple of years. Five long years later it finally became reality. I am grateful then to the patience of Jonathan with my, I am sure it seemed, perpetual “only 3 more months.”

My interest in addiction developed as a NIDA funded Research Fellow at McLean Hospital from 2005 to 2009. In 2005, I was working as a contract chemist at Polaroid, considering a career switch from industry to academic; though, at the then age of 47, I was not sure how feasible that might be. Although I had never met John Neumeyer I was aware of him and noticed he ran a medicinal chemistry group at McLean Hospital. John had been a professor at Northeastern University and had also started Research Biochemicals International, so I thought as one who had lived in both worlds, he might be able to offer some sound advice. Upon meeting with John I was surprised when he said he had a position open in his lab that would be funded by a NIDA Training Grant under Jack Mendelson and Nancy Mello. Though I knew very little about addiction it seemed like an ideal opportunity to fulfill my dream of conducting CNS research, so I accepted. Little did I realize that I was joining a research center started by pioneers in the study of addiction. During my stay at McLean I attended weekly research meetings where I was introduced to the arcane (at least to me) world of behavioral pharmacology. Luckily, I was surrounded by leaders in the study of rodent and primate behavior and addiction; Jack Bergman, Barak Caine, Steven Negus, and Nancy Mello, who were all very patient with explaining behavioral pharmacology to a simple organic chemist. It was probably the most interesting time of my scientific career, and I will be forever grateful for their guidance and patience. My biggest regret is that Jack Mendelson passed away shortly after I joined, so I never really got to know him. Unfortunately, Nancy also passed away in 2013, and so the torch has been passed.

In this book, I will attempt to convey my understanding of addiction to the general medicinal chemistry community. Primarily, this is a book written by an organic chemist for organic chemists. Addiction is a fascinating field of research with very real therapeutic outcomes that deserves more attention by medicinal chemists. As we will see, addiction research relies heavily on the use of animal models that mimic the different stages of addiction. A close working relationship between chemists and behavioral pharmacologists is therefore critical. To aid chemists interested in addiction, I have tried to reduce a complex subject to where it is understandable to those not fluent in the languages of human and nonhuman behavior and the structure and function of the brain. As such, I have taken some liberties during this reduction that experts in the different subjects may find too simplistic, and they will be right. My defense is that it is probably not necessary for a medicinal chemist to expertly understand the controversies and intricacies of self-administration versus conditioned place preference. It won't help making molecules and it is probably a more productive use of time and intellectual energy to have behavioral pharmacologists explain it over a cup of coffee. Nonetheless, some level of understanding is required if one is to correctly interpret pharmacology data in order to direct your efforts in the right direction.

The book is divided into two broad sections. The first section of Chapters 1–4 deals with general aspects of addiction, neuropharmacology, behavioral pharmacology, and drug development. The second section of Chapters 5–10 dives more deeply into medication development. Chapter 1 is a general discussion on the effects of addiction in society. It presents questions of what is addiction and how is it described. Chapter 2 covers the neurobiology and neurochemistry of addiction. This chapter looks at the important neurotransmitter and receptor systems involved in the development of addiction. The goal of the chapter is to provide a solid neurochemistry mechanistic understanding of how addictive drugs work and potential targets to treat addiction. The neurobiology of addiction is very complex and is beyond the scope of this book, and myself, to present it with the accuracy and depth it deserves. Fortunately, it is well covered in other books, most notably by Koob and Le Moal in Neurobiology of Addiction. I have concentrated on presenting it more from of a “systems biology” viewpoint with concise discussions on the important cellular and anatomical changes that occur in addiction. In order to help the reader fully understand results discussed in the subsequent chapters, a description of common behavioral pharmacology testing methods is presented in Chapter 3. It will be written with the assumption that the average reader has limited exposure to this area. Topics covered are animal models of the different stages of addiction, interpreting results, some pros and cons of rodent versus nonhuman primate models, and extrapolation of animal models to the human disease state. As an introduction to Chapters 5–10, Chapter 4 covers general approaches to drug development for the treatment of addiction. Special areas of concern relative to the treatment of CNS diseases such as the blood–brain barrier are discussed. While the majority of content in this chapter will be known to medicinal chemists, the non-chemist will hopefully find it informative.

In Chapters 5–10, we more extensively study each drug of abuse and the development of medications to treat its addictive properties. General themes in each chapter are some discussion on the chemistry and pharmacology of each drug of abuse, what drugs are currently approved and the drug's properties, and then finally the current medicinal chemistry strategies being conducted on medication development for the treatment of addiction. It needs to be emphasized that I have focused on drugs that have been tested in a clinical setting. This will exclude many interesting and important preclinical animal studies and the compounds that were developed to be used in those studies. I do not want to diminish the importance of this work; fortunately, it has already been amply reviewed, and I have tried to direct the reader to recent reviews covering the subjects. My emphasis on clinical studies is to show the reader what is known to actually work, or not work.

Some general comments on data and information in the book; first, the primary literature was used as much as possible. However, if not referenced then binding data and functional activity are taken from the PubChem or the NIMH Psychoactive Drug Screening Program databases. Drug properties, especially clinical ones, are taken from the National Library of Medicine database. I have also relied heavily on public information from the National Institute of Drug Abuse, Drug Enforcement Agency, and the United Nations Drug Abuse websites. A special acknowledgement is given to the individuals in each government agency who supply this valuable information to the public. Lastly, if a synthesis of a drug is not referenced, then it was taken from the book Pharmaceutical Substances: Syntheses, Patents and Applications of the most relevant AIPs, 5th edition.

On a more personal note, I would like to thank my parents and brothers for their patience and understanding for the missed Christmases, Ozark float trips, and High Sierra climbing as I tried to complete this book during semester breaks. Special thanks goes to my psychological consultants Sylvia Halperin, Ph.D., and Elissa Klienman, M.D., as well as to Anna Sole for the encouragement.

BRIAN S. FULTON

Somerville, MA2014

1WHAT IS DRUG ADDICTION?

I can resist everything except temptation

(Oscar Wilde)

It is a simple question with complicated answers. First, and foremost, drug addiction is a medical condition and should be viewed as such. Gone are the days when drug addiction, as with all mental illness, was simplistically viewed as a problem of “free will.” A simple answer to the question is when a person cannot stop using a substance (drug) even though they are fully aware the substance is destroying them. We will look at more specific descriptions of addiction later. We also will discuss the difference between addiction, abuse, and dependence. In the categorization of addiction, the user can be classified as being addicted to a single drug or to multiple drugs (e.g., alcohol and nicotine).

Complicating the situation is the fairly common phenomena of comorbidity. The term “comorbidity” describes two or more disorders occurring in the same person such as addiction comorbid with depression or schizophrenia comorbid with addiction.1 This will complicate the treatment strategy, for example, which disorder to treat first? Are they separate or linked? Did one precede the other? The clinician must take into account these factors. It may also be of importance to the medicinal chemist, especially if there is an underlying physiological commonality.

In this chapter, we will look at some of the societal effects of addiction and then look more closely at the distinct stages of addiction. Unless otherwise mentioned, all statistics in the upcoming discussion are taken from the National Institutes of Drug Abuse (NIDA) web site or from the 2012 NSDUH (National Survey on Drug Use and Health) study by the US Department of Health and Human Services.

In most literature addressed for law enforcement agencies, the medical profession, and for the general public, distinctions are often made between illicit and legal drugs. The illicit drugs are those we commonly associate with substance abuse: morphine or heroin, cocaine, methamphetamine, and marijuana. Legal drugs are alcohol, nicotine, prescription medications, and now in some states, marijuana. In this book, I will not make a distinction, that is, when the term “drug” or “drug addiction” is used, it can refer to both illicit and/or legal drugs. With regard to the practicing medicinal chemist who is developing medications for the treatment of addiction, the distinction is irrelevant.

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