EBOOK - Medicinal Chemistry 3rd Edition - A Molecular and Bilchemical Approach (Thomas Nogrady & Donald F. Weaver)


EBOOK - Hóa học dược phẩm - Phương pháp tiếp cận phân tử và hóa học (Thomas Nogrady & Donald F. Weaver) - 664 Trang.

There have been many changes in medicinal chemistry and molecular pharmacology since the second edition of this book was published in 1988. Accordingly, it has required extensive updating. This process was initiated in the Chemistry Department of Queen’s University, Kingston, Canada where Dr. Nico van Gelder, an Adjunct Emeritus Professor, introduced the now retired Thomas Nogrady to Donald Weaver, a medicinal chemist and clinical neurologist. Together, Weaver and Nogrady undertook the challenge of updating this book. In this way the third edition of Medicinal Chemistrywas started and the two authors have worked together to ensure a continuity in the style and content that has made this book popular among students and researchers alike.


CONTENTS:

I GENERAL MOLECULAR PRINCIPLES OF DRUG DESIGN
Introduction to Part I 5
Drug Design: A Conceptual Approach 5
Drug Design: A Practical Approach 7
Drug Design: The Humanitarian Approach 8
1. Basic Principles of Drug Design I—Drug Molecules:
Structure and Properties 9
1.1 Definition and Properties of a Drug Molecule 9
1.2 Physicochemical Properties of Drug Molecules 24
1.3 Shape (Geometric, Conformational, Topological, and Steric)
Properties of Drug Molecules 32
1.4 Stereochemical Properties of Drug Molecules 36
1.5 Electronic Properties of Drug Molecules 40
1.6 Predicting the Properties of Drug Molecules:
Quantum Mechanics and Molecular Mechanics 43
Selected References 63
2. Basic Principles of Drug Design II—Receptors:
Structure and Properties 67
2.1 The Receptor Concept and its History 67
2.2 The Nature of Receptors and Criteria for
Receptor Identity 68
2.3 Definitions of Drug–Receptor Binding Interactions 69
2.4 Definitions of Classical Binding Terms for
Drug–Receptor Interactions 75
2.5 Classical Theories of Drug–Receptor Binding Interactions 78
2.6 Experimental Quantification of Drug–Receptor
Binding Interactions 81
2.7 General Molecular Concepts of Drug Receptor Action 84
2.8 Receptor Action: Regulation, Metabolism,
and Dynamics 90
2.9 Receptor Types as Determined by Molecular
Mode of Action 92
2.10 Receptor Action: Mechanisms in Receptor
Signal Transduction 93
2.11 Selecting a Receptor Appropriate for Drug Design 96
2.12 The Clinical–Molecular Interface: The Concept
of Rational Polypharmacy 101
Selected References 103
3. Basic Principles of Drug Design III—Designing
Drug Molecules to Fit Receptors 106
3.1 Overall Strategy: The Multiphore Method of
Drug Design 106
3.2 Identification of a Lead Compound 108
3.3 Synthesis of a Lead Compound 128
3.4 Optimizing the Lead Compound:
The Pharmacodynamic Phase 134
3.5 Optimizing the Lead Compound: Pharmacokinetic
and Pharmaceutical Phases 146
3.6 From Lead Discovery to Clinical Trials:
The Concept of a “Useful Drug” 159
Selected References 163
Appendix 3.1: Basic Reactions for Drug Molecule Synthesis 166
II BIOCHEMICAL CONSIDERATIONS IN DRUG DESIGN:
FROM DRUGGABLE TARGETS TO DISEASES
Introduction to Part II 185
The Physiological Systems Approach 186
The Pathological Process Approach 186
The Molecular Messenger and Nonmessenger Target System 188
4. Messenger Targets for Drug Action I:
Neurotransmitters and Their Receptors 193
4.1 Overview of Relevant Neuroanatomy and Neurophysiology 193
4.2 Acetylcholine and the Cholinergic Receptors 204
4.3 Norepinephrine and the Adrenergic Receptors 218
4.4 Dopamine and the Dopaminergic Receptors 238
x MEDICINAL CHEMISTRY
4.5 Serotonin and the Serotonergic Receptors 249
4.6 Histamine and the Histamine Receptors 260
4.7 Inhibitory Amino Acid Neurotransmitters:
γ-Aminobutyric Acid (GABA) 270
4.8 Inhibitory Amino Acid Neurotransmitters: Glycine 281
4.9 Excitatory Amino Acid Neurotransmitters: Glutamate 283
4.10 Large-Molecule Neurotransmitters: Peptides 288
4.11 Small-Molecule Neurotransmitters: Gases
(Nitric Oxide, Carbon Monoxide) 291
4.12 Neuromodulators: Taurine and β-Alanine 296
4.13 Purinergic Neuromodulation and the
Adenosine Receptors 297
Selected References 299
5. Messenger Targets for Drug Action II: Hormones
and Their Receptors 310
5.1 Overview of Relevant Anatomy and Physiology
of Hormones 310
5.2 Steroid Hormones: Introduction 312
5.3 Steroid Hormones: Receptor Biochemistry 312
5.4 Steroid Hormones: Structure and Conformation of
Agonists and Antagonists 314
5.5 Steroid Hormones: Steroid Biosynthesis 315
5.6 Steroid Hormones: Cholesterol as a
Biosynthetic Precursor 316
5.7 Steroid Hormones: Sex Hormones—Introduction 320
5.8 Steroid Hormones: Sex Hormones—Estrogens 321
5.9 Steroid Hormones: Sex Hormones—Progestins
(Gestagens) 325
5.10 Steroid Hormones: Sex Hormones—Androgens 328
5.11 Steroid Hormones: Adrenocorticoids
(Adrenal Steroids)—Overview 332
5.12 Steroid Hormones: Adrenocorticoids—Glucocorticoids 332
5.13 Steroid Hormones: Adrenocorticoids—Mineralocorticoids 337
5.14 Peptide Hormones: Introduction 338
5.15 Peptide Hormones of the Brain 338
5.16 Peptide Hormones of the Anterior Pituitary 346
5.17 Peptide Hormones of the Posterior Pituitary 348
5.18 Peptide Hormones of the Opiate System 350
5.19 Peptide Hormones of the Thyroid and
Parathyroid Glands 359
5.20 Peptide Hormones of the Pancreas: Insulin and Glucagon 364
5.21 Peptide Hormones of the Kidney (Renin–Angiotensin
System) 371
5.22 Peptide Hormones of the Heart (Natriuretic Factors) 376
CONTENTS xi
5.23 Peptide Hormones and the Design of Drugs for Hypertension 378
5.24 Peptide and Steroid Hormones as Starting Points in
Drug Design 381
Selected References 382
6. Messenger Targets for Drug Action III:
Immunomodulators and Their Receptors 386
6.1 Overview of the Immune System as a Source of Drug Targets 386
6.2 Design of Immunosuppressive Drugs 392
6.3 Design of Immunomodulating Drugs 398
6.4 The Clinical–Molecular Interface: Collagen Diseases 403
Selected References 405
7. Nonmessenger Targets for Drug Action I:
Endogenous Cellular Structures 406
7.1 Cellular Structures: Relevant Anatomy and Physiology 406
7.2 Targeting Cell Membrane Structures: Lipid Component 409
7.3 Targeting Cell Membrane Structures: Protein Component 412
7.4 Targeting Cell Membrane Proteins: Voltage-Gated
Ion Channels 413
7.5 Targeting Cell Membrane Proteins: Ligand-Gated Ion Channels  432
7.6 Targeting Cell Membrane Proteins: Transmembrane
Transporter Proteins 433
7.7 Targeting Cellular Cytoplasmic Structures 439
7.8 Targeting Cell Nucleus Structures 441
Selected References 463
8. Nonmessenger Targets for Drug Action II:
Endogenous Macromolecules 465
8.1 Endogenous Macromolecules: Relevant Biochemistry 465
8.2 Proteins as Drugs and Drug Design Targets: Enzymes 483
8.3 Proteins as Drugs and Drug Design Targets: Non-Enzymes 513
8.4 Nucleic Acids as Drugs and Drug Design Targets 517
8.5 Lipids as Drugs and Drug Design Targets 519
8.6 Carbohydrates as Drugs and Drug Design Targets 528
8.7 Heterocycles as Drugs and Drug Design Targets 529
8.8 Inorganic Substances as Drugs and Drug Design Targets 532
Selected References 538
9. Nonmessenger Targets for Drug Action III:
Exogenous Pathogens and Toxins 543
9.1 Exogenous Pathogens as Targets
for Drug Design 543
9.2 Drug Design Targeting Prions 546
xii MEDICINAL CHEMISTRY
9.3 Drug Design Targeting Viruses 547
9.4 Drug Design Targeting Bacteria 559
9.5 Drug Design Targeting Fungi 581
9.6 Drug Design Targeting Parasites 584
9.7 The Clinical–Molecular Interface: Pneumonia 591
9.8 The Clinical–Molecular Interface: Meningitis and Encephalitis 592
9.9 Drug Design of Therapies and Antidotes for Toxins 593
Selected References 596
Appendix: Drugs Arranged by Pharmacological Activity 601
Index 629

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