Drug Discrimination: Applications to Medicinal Chemistry and Drug Studies

Drug discrimination: a practical guide to its contributions tothe invention of new chemical entities and evaluations of new orknown pharmacological agents

Drug discrimination can be described as a "drug detection"procedure that uses a pharmacologically active agent as thesubjective stimulus. Although the procedure does require someeffort to implement, it can be an extremely important tool forunderstanding drug action. Whereas medicinal chemists should cometo learn the types of information that drug discrimination studiescan offer, pharmacologists and psychologists might come to realizehow medicinal chemists can apply the types of information that theparadigm routinely provides. Drug Discrimination: Applications toMedicinal Chemistry and Drug Studies provides in–depth analyses ofthe nature and use of drugs as discriminative stimuli and bridgessome of the numerous gaps between medicinal chemistry,pharmacology, and psychology.

Stressing the practical aspects of drug discrimination,including types of procedures, study design, data, andinterpretation, the book details the advantages and limitations ofdrug discrimination studies versus other pharmacologic evaluations.Practical information from leading researchers in the fieldaddresses specific topics and techniques that are of interest indrug discovery, evaluation, and development.

A groundbreaking new guide to the applications of drugdiscrimination studies for medicinal chemistry and neuroscience,Drug Discrimination is essential for any scientist, researcher, orstudent whose interests involve the design, development, and/oraction of drugs acting at the level of the central nervoussystem.

Preface xv

Contributors xix

Part I 1
Richard A. Glennon and Richard Young

1. An Introduction to Drug Discrimination 3

A. General Scope and Introductory Comments 3

B. Background and Utility of the Drug Discrimination Paradigm7

C. Drug Discrimination: A Synopsis of the Approach 10

D. Drug Discrimination and Drugs of Abuse 11

E. Advantage of the Drug Discrimination Procedure 14

2. Methodological Considerations 19

A. Apparatus 19

B. Subjects 22

C. Operant Conditioning 23

3. Drug Discrimination: Practical Considerations 41

A. Drugs as Discriminative Stimuli 42

B. Choice of Dose and Pre–session Injection Interval 49

C. Discrimination Training Procedure 51

D. Discrimination Data 52

E. Testing 60

F. Data Analysis and Interpretations 78

G. Selected Topics 99

4. Role of Stereochemistry in Drug Discrimination Studies129

A. Structural Isomers: Introduction 129

B. Constitutional Isomers 130

C. Stereoisomers 136

5. Drug Discrimination and in Vivo Structure–ActivityRelationships 163

A. Structure–Activity Caveats 163

B. Phenylalkylamines Hallucinogens and Stimulants 165

C. Benzodiazepines 175

D. Neuronal Nicotinic Acetylcholinergic receptor Agents 177

E. Aminotetralins 178

6. Drug Discrimination and Mechanisms of Drug Action183

A. Early Considerations 184

B. Classical Hallucinogens 186

C. Amphetamine–Related Stimulants 192

D. MDA and MDMA 198

E. PMMA 204

F. a–Ethyltryptamine 205

G. Anxiolytic Agents 206

7. Drug Discrimination and Development of Novel Agents andPharmacological Tools 217

A. Applicability and General Comments 217

B. Novel 5–HT2 Serotonin Receptor Antagonists 218

C. 5–HT2 Serotonin Receptor Agonists and Radioligands222

D. Aminotetralins as 5–HT1A Serotonin ReceptorLigands 225

E. Arylpiperazine 5–HT1A Serotonin ReceptorAntagonists 225

F. MD–354 (meta–Chlorophenylguanidine): A5–HT3 Serotonin Receptor Agonist 227

G. Loperamide and Risperidone: Clinical Successes 230

Appendix 235

Part II 239

8. Perceptual Drug Discriminative Aspects of theEndocannabinoid Signaling System in Animals and Man 241
Torbjörn U. C. Järbe

A. Introduction 242

B. Brief Synopsis of the Endocannabinoid Signaling System (ECS)243

C. Cannabinoids/Cannabinergics and Drug Discrimination 244

D. Experimental Procedures and Species 244

E. Training Drugs 247

F. Procedural Considerations 253

G. Intended and Unintended Bias in DrugDiscrimination 254

H. Origin of the Drug Stimulus and Sensory Mediation 254

I. Acquired Differences in Drug Sensitivity 255

J. Pharmacological Specificity 258

K. Phytocannabinoids and Metabolites 260

L. Endocannabinoid Ligands and the ECS 262

M. ECS Interactions with Other Signaling Systems 265

N. Conclusions/Summary 266

O. Addendum 268

9. Discriminative Stimulus Properties of Receptor Antagonists287
Joseph H. Porter

A. Introduction 288

B. Adrenoceptor Antagonists 289

C. Antihistamines 292

D. Atypical Antipsychotic Drugs 294

E. Benzodiazepine Antagonists 299

F. Cannabinoid Antagonists 299

G. Cholinergic Antagonists 301

H. Dopamine Antagonists 302

I. GABAergic Antagonists 305

J. Opiate Antagonists 306

K. Serotonergic Anatagonists 310

L. Summary 312

10. The Discrimination of Drug Mixtures 323
Ian P. Stolerman

A. Introduction 324

B. Functional Models for the Discriminative Effects of DrugMixtures 326

C. Initial Studies: Mixtures of Nicotine plus Midazolam 328

D. Characteristics of Diverse Drug Discriminations 329

E. Role of Training Doses 334

F. Variations in Functional Relationships: The Role of TrainingParadigm 336

G. Antagonism of Mixture Cues and Training with Agonists plusAntagonists 342

H. Associative Processes 345

I. Investigations on the Ethanol Cue as a Compound Stimulus348

J. Discussion 351

11. Making the Right Choice: Lessons from Drug Discriminationfor Research on Drug Reinforcement and Drug Self–Administration361
S. Stevens Negus and Matthew L. Banks

A. Operant Conditioning to Study the Stimulus Properties ofDrugs 362

B. Choice Procedures in Studies of Drug Reinforcement: Lessonsfrom Drug Discrimination 371

C. Summary 380

12. Inhalant Drug Discrimination Studies in Phesus Monkeys:Drug Dependence and Withdrawal 417
Jun–Xu Li, Lisa R. Gerak, and Charles P. France

A. Introduction 417

B. Some Factors Impacting the Discriminative Stimulus Effects ofDrugs 418

C. Drug Interactions: Acute Dosing 420

D. Drug Interactions: Chronic Dosing 423

E. Summary and Conclusions 427

14. Human Drug Discrimination: Methodological Considerationsand Application to Elucidating the Neuropharmacology ofAmphetamines 431
Craig R. Rush, Andrea R. Vansickel, and William W.Stoops

A. Introduction 432

B. Methodological Issues to Consider when Designing andConducting a Human Drug Discrimination Experiment 433

C. Using Human Drug Discrimination to Elucidate theNeuropharmacology of Amphetamines 444

D. The Future of Human Drug Discrimination 449

15. Nicotine Discrimination in Humans 463
Kenneth A. Perkins

A. Introduction 464

B. Basic Methods of Nicotine Discrimination Research in Humans465

C. Basic Parameters of Nicotine Discrimination 468

D. Individual Differences and Moderators of NicotineDiscrimination 473

E. Conclusions 477

16. Drug Discrimination: A Perspective 483
The late Francis C. Colpaert

A. State Dependence and Drug Discrimination 484

B. Drug Discrimination in Receptor Pharmacology 484

C. Drug Discrimination and Subjective Drug Effects 485

D. New Concepts of Opiate Tolerance, Signal Processing, Pain,and Analgesia 486

E. Drug Discrimination: An Elementary Particle of Behavior andMore 488

F. When Dependent Variables Chose Their Pharmacology 491

G. Two Further Mysteries 491

H. Epilogue 492

Index 497

Richard Glennon is Chair of the Department of MedicinalChemistry at Virginia Commonwealth University. He is the author ofover four hundred scientific publications and book chapters.

Richard Young is an Associate Professor in the Departmentof Medicinal Chemistry at Virginia Commonwealth University.Previously, he worked in the pharmaceutical industry at Ayerst andA. H. Robins (both now Pfizer).