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FOYE'S Principles of Medicinal Chemistry SIXTH EDITION Edited By THOMAS L LEMKE, P H D Professor Emeritus College of Pharmacy University of Houston Houston, Texas DAVID A. WILLIAMS, P H D Professor Emeritus of Chemistry Massachusetts College of Pharmacy and Health Sciences Boston, Massachusetts Assistant Editors VICTORIA F. ROCHE, P H D Senior Associate Dean School of Pharmacy and Health Professions Creighton University Omaha, Nebraska S. WILLIAM ZITO, P H D Professor of Pharmaceutical Sciences College of Pharmacy and Allied Health Professions St. John's University Jamaica, Neiv York © . Wolters Kluwer Lippincott Williams & Wilkins Health Philadelphia • Baltimore • New York • London Buenos Aires • Hong Kong • Sydney • Tokyo CONTENTS Historical Perspective of Medicinal Chemistry 1 Chapter 14 JOHN L NEUMEYER PART I: PRINCIPLES OF DRUG DISCOVERY Chapter 1 Chapter 2 Drug Discover)' from Natural Products A. DOUGLAS KINGHORN Drug Design and Relationship of Functional Groups to Pharmacologic Activity 26 JAMESJ. KNITTEL AND ROBIN M. ZAVOD Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission 417 RICHARD A. GLENNON AND MALGORZATA DUKAT-GLENNON Amino Acid Neurotransmitters in the Central Nervous System 444 TIMOTHYJ. MAHER Inhibitors of Nerve Conduction: Local Anesthetics 462 MATTHIAS C. LU Phosphodiesterase Inhibitors KEVIN DALBY 12 Chapter 15 Chapter 16 Chapter 3 Molecular Modeling and In Silico Drug Design 54 XIANG-QUN (SEAN) XIE Receptors and Drug Action 85 TIMOTHY A. MAHER AND DAVID A. JOHNSON Chapter 17 480 Chapter 4 Chapter 5 PART III: PHARMACODYNAMIC AGENTS Section 1: Drugs Affecting Central Nervous System Chapter 18 Chapter 19 Chapter 20 Chapter 21 Chapter 22 General Anesthetics 490 TIMOTHYJ. MAHER Drug Discovery Through Enzyme Inhibition 99 STEPHEN KERR Pharmaceutical Biotechnology— From Nucleic Acids to Personalized Medicine 115 RONALD E. REID AND ROBERT D. SINDELAR Sedative-Hypnotics WILLIAM SOINE Antiseizure Agents BARBARA LEDUC Antidepressants DAVID A. WILLIAMS 504 521 Chapter 6 547 Chapter 7 Chapter 8 Chapter 9 Peptide and Protein Drugs MICHAEL MOKOTOFF 175 201 Antisense Therapeutic Agents MARILYN SPEEDIE Psychotherapeutic Drugs: Antipsychotic and Anxiolytic Agents 601 RAYMOND G. BOOTH Hallucinogens, Stimulants and Related Drugs of Abuse 631 RICHARD A. GLENNON Chapter 23 Physicochemical and Biopharmaceutical Properties of Drug Substances and Pharmacokinetics 210 SUNILS.JAMBHEKAR Chapter 24 Chapter 25 Opioid Analgesics DAVIDS. FRIES 652 Chapter 10 Chapter 11 Drug Metabolism DAVID A. WILLIAMS 253 327 U. S. Drug Regulation: An Overview DOUGLASJ. PISANO Drugs Used to Treat Neuromuscular Disorders: Antiparkinsonian and Spasmolytic Agents 679 RAYMOND G. BOOTH PART II: DRUG RECEPTORS AFFECTING NEUROTRANSMISSION AND ENZYMES AS CATALYTIC RECEPTORS Section 2: Drugs Affecting the Cardiovascular System Chapter 26 340 Chapter 27 Chapter 28 Cardiac Agents: Cardiac Glycosides, Antianginal, and Antiarrhythmic Drugs l 698 AHMED S. MEHANNA Diuretics 722 GARYO. RANKIN Overview of Drug Receptors: A Perspective DAVIDJ.TRIGGLE Chapter 12 Drugs Affecting Cholinergic Neurotransmission 361 E. KIM FIFER Adrenergic Receptors and Drugs Affecting Adrenergic Neurotransmission 392 ROBERT K. GRIFFITH Chapter 13 Angiotensin-Converting Enzyme Inhibitors, Antagonists and Calcium Blockers 738 MARC HARROLD XIV CONTENTS Chapter 29 Central and Peripheral Sympatholytics and Vasodilators 769 DAVID A. WILLIAMS Antihyperlipoproteinemics and Inhibitors of Cholesterol Biosynthesis 797 MARC HARROLD Antithrombotics, Thrombolytics, Coagulants, and Plasma Extenders 820 MATTHIAS C. LU AND THOMAS L LEMKE Section 5: Chemotherapeutic Agents Chapter 38 Antibiotics and Antimicrobial Agents 1028 LESTER A. MITSCHER, THOMAS L LEMKE, AND ELMERJ. GENTRY Antiparasitic Agents THOMAS L LEMKE 1084 Chapter 30 Chapter 39 Chapter 40 Chapter 41 Chapter 42 Chapter 43 Chapter 31 Antifungal Agents 1112 ROBERT K. GRIFFITH Antimycobacterial Agents THOMAS L LEMKE Cancer and Chemotherapy VICTORIA F. ROCHE Antiviral Agents and Protease Inhibitors 1193 PATRICK M. WOSTER 1127 1147 Section 3: Drugs Affecting the Hormonal Systems Chapter 32 Insulin and Drugs Used for the Treatment of Diabetes 855 ROBIN M. ZAVODJOHN L. KRSTENANSKY, AND BRUCE L. CURRIE Adrenocorticoids 877 DUANE D. MILLER, ROBERTW. BRUEGGEMEIER AND JAMES T. DALTON Thyroid Function and Thyroid Drugs ALI R. BANIJAMALI Calcium Homeostasis ROBIN M. ZAVOD 935 913 Chapter 33 PART IV: DISEASE STATE MANAGEMENT Chapter 44 Asthma and Chronic Obstructive Pulmonary Disease 1230 S. WILLIAM ZITO Men's Health 1265 DUANE D. MILLER, ROBERTW. BRUEGGEMEIER, AND JAMES T. DALTON Women's Health ROBIN M. ZAVOD 1301 Chapter 34 Chapter 35 Chapter 45 Section 4: Drugs Affecting the Immune Systems Chapter 36 Nonsteroidal Anti-Inflammatory Drugs 954 RONALD BORNE, MARK LEVI, NORMAN WILSON Antihistamines and Related Antiallergic and Antiulcer Agents 1004 WENDELLNELSON Chapter 46 Chapter 37 Appendix A: pKa Values for Some Drugs and Miscellaneous Organic Acids and Bases 1343 Appendix B: pH Values for Tissue Fluids 1354 Drug Index 1355 Subject Index 1361