| Preface |
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xiii | |
| Preface to the Third Edition |
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xv | |
| Preface to the Second Edition |
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xvii | |
| Preface to the First Edition |
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xix | |
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1 | (1) |
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1.2 What Is Pharmacology? |
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1 | (2) |
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3 | (2) |
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1.4 Pharmacological Test Systems |
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5 | (2) |
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1.5 The Nature of Drug Receptors |
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7 | (1) |
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1.6 Pharmacological Intervention and the Therapeutic Landscape |
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8 | (1) |
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1.7 System-Independent Drug Parameters: Affinity and Efficacy |
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9 | (2) |
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11 | (2) |
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1.9 The Langmuir Adsorption Isotherm |
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13 | (2) |
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15 | (1) |
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1.11 Dose-Response Curves |
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16 | (3) |
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1.11.1 Potency and Maximal Response |
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17 | (1) |
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1.11.2 p-Scales and the Representation of Potency |
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18 | (1) |
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1.12 Chapter Summary and Conclusions |
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19 | (1) |
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1.13 Derivations: Conformational Selection as a Mechanism of Efficacy |
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20 | (1) |
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20 | (1) |
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2 How Different Tissues Process Drug Response |
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2.1 Drug Response as Seen Through the "Cellular Veil" |
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21 | (2) |
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2.2 The Biochemical Nature of Stimulus-Response Cascades |
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23 | (2) |
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2.3 The Mathematical Approximation of Stimulus-Response Mechanisms |
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25 | (2) |
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2.4 System Effects on Agonist Response: Full and Partial Agonists |
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27 | (3) |
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2.5 Differential Cellular Response to Receptor Stimulus |
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30 | (5) |
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2.5.1 Choice of Response Pathway |
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31 | (1) |
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2.5.2 Augmentation or Modulation of Stimulus Pathway |
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31 | (1) |
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2.5.3 Differences in Receptor Density |
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32 | (1) |
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2.5.4 Target-Mediated Trafficking of Stimulus |
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33 | (2) |
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2.6 Receptor Desensitization and Tachyphylaxis |
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35 | (2) |
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2.7 The Measurement of Drug Activity |
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37 | (1) |
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2.8 Advantages and Disadvantages of Different Assay Formats |
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37 | (1) |
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2.9 Drug Concentration as an Independent Variable |
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38 | (2) |
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2.9.1 Dissimulation in Drug Concentration |
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38 | (2) |
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2.9.2 Free Concentration of Drug |
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40 | (1) |
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2.10 Chapter Summary and Conclusions |
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40 | (1) |
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41 | (4) |
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2.11.1 Series Hyperbolae Can Be Modeled by a Single Hyperbolic Function |
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41 | (1) |
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2.11.2 Successive Rectangular Hyperbolic Equations Necessarily Lead to Amplification |
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41 | (1) |
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2.11.3 Saturation of Any Step in a Stimulus Cascade by Two Agonists Leads to Identical Maximal Final Responses for the Two Agonists |
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41 | (1) |
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2.11.4 Procedure to Measure Free Drug Concentration in the Receptor Compartment |
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42 | (1) |
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42 | (3) |
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45 | (1) |
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46 | (1) |
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3.3 The Use of Mathematical Models in Pharmacology |
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47 | (1) |
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3.4 Some Specific Uses of Models in Pharmacology |
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47 | (2) |
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3.5 Classical Model of Receptor Function |
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49 | (1) |
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3.6 The Operational Model of Receptor Function |
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50 | (1) |
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51 | (1) |
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3.8 The Ternary Complex Model |
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52 | (1) |
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3.9 The Extended Ternary Complex Model |
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52 | (1) |
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3.10 Constitutive Receptor Activity and Inverse Agonism |
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53 | (2) |
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3.11 The Cubic Ternary Complex Model |
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55 | (1) |
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3.12 Multistate Receptor Models and Probabilistic Theory |
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56 | (1) |
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3.13 Chapter Summary and Conclusions |
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57 | (1) |
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57 | (6) |
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3.14.1 Radioligand Binding to Receptor Dimers Demonstrating Cooperative Behavior |
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58 | (1) |
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3.14.2 Effect of Variation in an HIV-1 Binding Model |
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58 | (1) |
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3.14.3 Derivation of the Operational Model |
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59 | (1) |
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3.14.4 Operational Model Forcing Function for Variable Slope |
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60 | (1) |
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3.14.5 Derivation of Two-State Theory |
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60 | (1) |
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3.14.6 Derivation of the Extended Ternary Complex Model |
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61 | (1) |
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3.14.7 Dependence of Constitutive Activity on Receptor Density |
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61 | (1) |
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3.14.8 Derivation of the Cubic Ternary Complex Model |
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61 | (1) |
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62 | (1) |
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4 Pharmacological Assay Formats: Binding |
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4.1 The Structure of This Chapter |
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63 | (1) |
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4.2 Binding Theory and Experiment |
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63 | (9) |
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65 | (2) |
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4.2.2 Displacement Binding |
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67 | (4) |
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4.2.3 Kinetic Binding Studies |
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71 | (1) |
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4.3 Complex Binding Phenomena: Agonist Affinity from Binding Curves |
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72 | (3) |
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4.4 Experimental Prerequisites for Correct Application of Binding Techniques |
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75 | (3) |
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4.4.1 The Effect of Protein Concentration on Binding Curves |
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75 | (2) |
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4.4.2 The Importance of Equilibration Time for Equilibrium between Two Ligands |
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77 | (1) |
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4.5 Chapter Summary and Conclusions |
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78 | (1) |
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79 | (6) |
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4.6.1 Displacement Binding: Competitive Interaction |
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79 | (1) |
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4.6.2 Displacement Binding: Noncompetitive Interaction |
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79 | (1) |
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4.6.3 Displacement of a Radioligand by an Allosteric Antagonist |
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80 | (1) |
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4.6.4 Relationship between IC50 and K1 for Competitive Antagonists |
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80 | (1) |
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4.6.5 Maximal Inhibition of Binding by an Allosteric Antagonist |
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81 | (1) |
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4.6.6 Relationship between IC50 and K1 for Allosteric Antagonists |
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81 | (1) |
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4.6.7 Two-Stage Binding Reactions |
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81 | (1) |
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4.6.8 Effect of G-protein Coupling on Observed Agonist Affinity |
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82 | (1) |
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4.6.9 Effect of Excess Receptor in Binding Experiments: Saturation Binding Curve |
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82 | (1) |
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4.6.10 Effect of Excess Receptor in Binding Experiments: Displacement Experiments |
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82 | (1) |
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82 | (3) |
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5 Agonists: The Measurement of Affinity and Efficacy in Functional Assays |
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5.1 Functional Pharmacological Experiments |
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85 | (1) |
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5.2 The Choice of Functional Assays |
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86 | (4) |
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5.3 Recombinant Functional Systems |
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90 | (3) |
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5.4 Functional Experiments: Dissimulation in Time |
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93 | (2) |
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5.5 Experiments in Real Time Versus Stop-Time |
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95 | (1) |
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5.6 Quantifying Agonism: The Black-Leff Operational Model of Agonism |
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96 | (6) |
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5.6.1 Affinity-Dependent versus Efficacy-Dependent Agonist Potency |
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98 | (3) |
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5.6.2 Secondary and Tertiary Testing of Agonists |
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101 | (1) |
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102 | (5) |
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5.7.1 Receptor Selectivity |
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107 | (1) |
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5.8 Null Analyses of Agonism |
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107 | (7) |
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107 | (3) |
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110 | (4) |
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5.9 Chapter Summary and Conclusions |
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114 | (1) |
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114 | (5) |
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5.10.1 Relationship Between the EC50 and Affinity of Agonists |
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114 | (1) |
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5.10.2 Method of Barlow, Scott, and Stephenson for Affinity of Partial Agonists |
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115 | (1) |
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5.10.3 Maximal Response of a Partial Agonist Is Dependent on Efficacy |
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115 | (1) |
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5.10.4 System Independence of Full Agonist Potency Ratios |
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115 | (1) |
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5.10.5 Measurement of Agonist Affinity: Method of Furchgott |
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115 | (1) |
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116 | (3) |
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6 Orthosteric Drug Antagonism |
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119 | (1) |
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6.2 Kinetics Of Drug-Receptor Interaction |
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120 | (2) |
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6.3 Surmountable Competitive Antagonism |
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122 | (12) |
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122 | (4) |
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6.3.2 Patterns of Dose-Response Curves That Preclude Schild Analysis |
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126 | (1) |
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6.3.3 Best Practice for the Use of Schild Analysis |
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127 | (1) |
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6.3.4 Analyses for Inverse Agonists in Constitutively Active Receptor Systems |
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128 | (3) |
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6.3.5 Analyses for Partial Agonists |
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131 | (2) |
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6.3.6 The Method of Lew and Angus: Nonlinear Regressional Analysis |
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133 | (1) |
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6.4 Noncompetitive Antagonism |
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134 | (4) |
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6.5 Agonist-Antagonist Hemi-Equilibria |
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138 | (1) |
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139 | (2) |
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6.7 Antagonist Receptor Coverage: Kinetics of Dissociation |
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141 | (3) |
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6.7.1 Estimating Antagonist Dissociation with Hemi-Equilibria |
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142 | (2) |
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6.8 Blockade of Indirectly Acting Agonists |
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144 | (1) |
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6.9 Irreversible Antagonism |
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144 | (2) |
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146 | (3) |
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6.11 Chapter Summary and Conclusions |
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149 | (1) |
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149 | (6) |
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6.12.1 Derivation of the Gaddum Equation for Competitive Antagonism |
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149 | (1) |
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6.12.2 Derivation of the Gaddum Equation for Noncompetitive Antagonism |
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150 | (1) |
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6.12.3 Derivation of the Schild Equation |
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150 | (1) |
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6.12.4 Functional Effects of an Inverse Agonist with the Operational Model |
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150 | (1) |
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6.12.5 pA2 Measurement for Inverse Agonists |
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151 | (1) |
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6.12.6 Functional Effects of a Partial Agonist with the Operational Model |
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151 | (1) |
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6.12.7 pA2 Measurements for Partial Agonists |
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151 | (1) |
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6.12.8 Method of Stephenson for Partial Agonist Affinity Measurement |
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152 | (1) |
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6.12.9 Derivation of the Method of Gaddum for Noncompetitive Antagonism |
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152 | (1) |
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6.12.10 Relationship of pA2 and pKB for Insurmountable Orthosteric Antagonism |
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152 | (1) |
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6.12.11 Resultant Analysis |
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153 | (1) |
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6.12.12 Blockade of Indirectly Acting Agonists |
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153 | (1) |
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6.12.13 Chemical Antagonism: Abstraction of Agonist Concentration |
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153 | (1) |
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6.12.14 Chemical Antagonism: Abstraction of Antagonist Concentration |
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154 | (1) |
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154 | (1) |
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155 | (1) |
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7.2 The Nature of Receptor Allosterism |
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155 | (3) |
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7.3 Unique Effects of Allosteric Modulators |
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158 | (4) |
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7.4 Functional Study of Allosteric Modulators |
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162 | (13) |
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7.4.1 Phenotypic Allosteric Modulation Profiles |
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166 | (1) |
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166 | (1) |
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7.4.3 Affinity of Allosteric Modulators |
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167 | (1) |
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7.4.4 Negative Allosteric Modulators (NAMs) |
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168 | (4) |
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7.4.5 Positive Allosteric Modulators (PAMs) |
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172 | (2) |
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7.4.6 Optimal Assays for Allosteric Function |
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174 | (1) |
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7.5 Methods for Detecting Allosterism |
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175 | (2) |
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7.6 Chapter Summary and Conclusions |
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177 | (1) |
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178 | (3) |
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7.7.1 Allosteric Model of Receptor Activity |
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178 | (1) |
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7.7.2 Effects of Allosteric Ligands on Response: Changing Efficacy |
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178 | (1) |
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7.7.3 Schild Analysis for Allosteric Antagonists |
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179 | (1) |
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179 | (2) |
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8 The Optimal Design of Pharmacological Experiments |
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181 | (1) |
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8.2 The Optimal Design of Pharmacological Experiments |
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181 | (16) |
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182 | (6) |
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188 | (7) |
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8.2.3 Orthosteric vs. Allosteric Mechanisms |
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195 | (1) |
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8.2.4 Target Coverage In Vivo |
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196 | (1) |
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8.3 Null Experiments and Fitting Data to Models |
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197 | (2) |
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8.4 Interpretation of Experimental Data |
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199 | (3) |
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8.5 Predicting Therapeutic Activity in All Systems |
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202 | (6) |
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203 | (1) |
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204 | (2) |
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8.5.3 Kinetics of Target Coverage |
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206 | (1) |
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8.5.4 Drug Combinations In Vivo |
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206 | (2) |
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8.6 Summary and Conclusions |
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208 | (1) |
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209 | (4) |
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8.7.1 IC50 Correction Factors: Competitive Antagonists |
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209 | (1) |
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8.7.2 Relationship of pA2 and pKB for Insurmountable Orthosteric Antagonism |
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209 | (1) |
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8.7.3 Relationship of pA2 and pKB for Insurmountable Allosteric Antagonism |
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210 | (1) |
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210 | (3) |
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213 | (1) |
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213 | (1) |
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9.3 The Chemistry of "Druglike" Character |
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214 | (4) |
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218 | (25) |
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219 | (6) |
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9.4.2 Route of Drug Administration |
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225 | (2) |
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9.4.3 General Pharmacokinetics |
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227 | (2) |
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229 | (3) |
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232 | (2) |
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9.4.6 Volume of Distribution and Half Life |
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234 | (6) |
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240 | (2) |
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242 | (1) |
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9.5 Nonlinear Pharmacokinetics |
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243 | (1) |
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244 | (3) |
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9.7 Practical Pharmacokinetics |
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247 | (2) |
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247 | (2) |
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9.8 Placement of Pharmacokinetic Assays in Discovery and Development |
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249 | (3) |
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9.9 Summary and Conclusions |
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252 | (3) |
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253 | (2) |
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255 | (6) |
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261 | (10) |
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10.2.1 Drug-Drug Interactions |
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261 | (9) |
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10.2.2 Direct Hepatotoxicity |
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270 | (1) |
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271 | (1) |
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272 | (1) |
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10.5 hERG Activity and Torsades De Pointes |
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273 | (1) |
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10.6 Autonomic Receptor Profiling |
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273 | (1) |
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10.7 General Pharmacology |
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274 | (1) |
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274 | (4) |
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10.9 Summary and Conclusions |
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278 | (3) |
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279 | (2) |
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11 The Drug Discovery Process |
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11.1 Some Challenges for Modem Drug Discovery |
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281 | (1) |
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11.2 Target-Based Drug Discovery |
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282 | (9) |
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11.2.1 Target Validation and the Use of Chemical Tools |
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283 | (2) |
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11.2.2 Recombinant Systems |
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285 | (1) |
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11.2.3 Defining Biological Targets |
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286 | (5) |
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11.3 Systems-Based Drug Discovery |
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291 | (5) |
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294 | (2) |
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11.4 In vivo Systems, Biomarkers, and Clinical Feedback |
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296 | (1) |
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11.5 Types of Therapeutically Active Ligands: Polypharmacology |
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297 | (3) |
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11.6 Pharmacology in Drug Discovery |
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300 | (2) |
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11.7 Chemical Sources for Potential Drugs |
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302 | (5) |
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11.8 Pharmacodynamics and High-Throughput Screening |
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307 | (7) |
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314 | (2) |
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316 | (2) |
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11.11 Summary and Conclusions |
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318 | (3) |
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318 | (3) |
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12 Statistics and Experimental Design |
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12.1 Structure of This Chapter |
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321 | (1) |
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321 | (1) |
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12.3 Descriptive Statistics: Comparing Sample Data |
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321 | (9) |
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12.3.1 Gaussian Distribution |
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322 | (1) |
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12.3.2 Populations and Samples |
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322 | (2) |
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12.3.3 Confidence Intervals |
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324 | (1) |
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325 | (1) |
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12.3.5 One-Way Analysis of Variance |
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326 | (1) |
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12.3.6 Two-Way Analysis of Variance |
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327 | (1) |
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12.3.7 Regression and Correlation |
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327 | (2) |
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12.3.8 Detection of Single Versus Multiple Populations |
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329 | (1) |
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12.4 How Consistent are Experimental Data with Models? |
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330 | (16) |
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12.4.1 Comparison of Data to Models: Choice of Model |
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330 | (2) |
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12.4.2 Curve Fitting: Good Practice |
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332 | (2) |
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12.4.3 Outliers and Weighting Data Points |
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334 | (2) |
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12.4.4 Overextrapolation of Data |
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336 | (1) |
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12.4.5 Hypothesis Testing: Examples with Dose-Response Curves |
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337 | (3) |
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12.4.6 One Curve or Two? Detection of Differences in Curves |
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340 | (1) |
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12.4.7 Asymmetrical Dose-Response Curves |
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341 | (1) |
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12.4.8 Comparison of Data to Linear Models |
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342 | (1) |
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12.4.9 Is a Given Regression Linear? |
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342 | (1) |
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12.4.10 One or More Regression Lines? Analysis of Covariance |
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343 | (3) |
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12.5 Comparison of Samples to "Standard Values" |
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346 | (1) |
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12.5.1 Comparison of Means by Two Methods or in Two Systems |
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346 | (1) |
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12.5.2 Comparing Assays/Methods with a Range of Ligands |
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347 | (1) |
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12.6 Experimental Design and Quality Control |
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347 | (3) |
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12.6.1 Detection of Difference in Samples |
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347 | (1) |
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348 | (2) |
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12.7 Chapter Summary and Conclusions |
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350 | (1) |
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350 | (1) |
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13 Selected Pharmacological Methods |
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351 | (2) |
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13.1.1 Saturation Binding |
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351 | (1) |
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13.1.2 Displacement Binding |
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351 | (2) |
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353 | (20) |
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13.2.1 Determination of Equiactive Concentrations on Dose-Response Curves |
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353 | (2) |
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13.2.2 Method of Barlow, Scott, and Stephenson for Measurement of the Affinity of a Partial Agonist |
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355 | (1) |
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13.2.3 Method of Furchgott for the Measurement of the Affinity of a Full Agonist |
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356 | (1) |
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13.2.4 Schild Analysis for the Measurement of Competitive Antagonist Affinity |
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357 | (2) |
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13.2.5 Method of Stephenson for Measurement of Partial Agonist Affinity |
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359 | (2) |
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13.2.6 Method of Gaddum for Measurement of Noncompetitive Antagonist Affinity |
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361 | (1) |
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13.2.7 Method for Estimating Affinity of Insurmountable Antagonist (Dextral Displacement Observed) |
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362 | (1) |
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13.2.8 Resultant Analysis for Measurement of Affinity of Competitive Antagonists with Multiple Properties |
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363 | (1) |
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13.2.9 Measurement of the Affinity and Maximal Allosteric Constant for Allosteric Modulators Producing Surmountable Effects |
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364 | (4) |
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13.2.10 Method for Estimating Affinity of Insurmountable Antagonist (No Dextral Displacement Observed): Detection of Allosteric Effect |
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368 | (1) |
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13.2.11 Measurement of pKB for Competitive Antagonists from a plC50 |
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369 | (4) |
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14 Exercises in Pharmacodynamics and Pharmacokinetics |
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|
373 | (1) |
|
|
|
373 | (10) |
|
14.2.1 Agonism: Structure-Activity Relationships |
|
|
373 | (1) |
|
14.2.2 Prediction of Agonist Effect |
|
|
374 | (1) |
|
|
|
375 | (1) |
|
|
|
376 | (1) |
|
14.2.5 Ordering of Affinity and Efficacy in Agonist Series |
|
|
376 | (1) |
|
14.2.6 Kinetics of Agonism |
|
|
376 | (1) |
|
14.2.7 Affinity-Dominant versus Efficacy-Dominant Agonists |
|
|
377 | (2) |
|
14.2.8 Agonist Affinities and Potencies Do Not Correlate |
|
|
379 | (1) |
|
14.2.9 Lack of Agonist Effect |
|
|
380 | (2) |
|
14.2.10 Assay-Specific Agonism |
|
|
382 | (1) |
|
|
|
383 | (8) |
|
14.3.1 Antagonist Potency and Kinetics: Part A |
|
|
383 | (2) |
|
14.3.2 Antagonist Potency in plC50 Format (Kinetics Part B) |
|
|
385 | (1) |
|
14.3.3 Mechanism of Antagonist Action (Kinetics Part C) |
|
|
386 | (1) |
|
14.3.4 Mechanism of Antagonist Action: Curve Patterns |
|
|
386 | (1) |
|
14.3.5 Mechanism of Action: Incomplete Antagonism |
|
|
387 | (2) |
|
14.3.6 plC50 Mode: Antagonism Below Basal |
|
|
389 | (1) |
|
14.3.7 Secondary Effects of Antagonists |
|
|
390 | (1) |
|
14.3.8 Antagonist Potency Variably Dependent on Agonist Concentration |
|
|
390 | (1) |
|
14.4 In vitro--In vivo Transitions and General Discovery |
|
|
391 | (5) |
|
14.4.1 "Silent Antagonism" |
|
|
391 | (1) |
|
|
|
392 | (1) |
|
14.4.3 Marking Relevant Agonism |
|
|
393 | (1) |
|
14.4.4 In vitro---In vivo Correspondence of Activity |
|
|
394 | (1) |
|
14.4.5 Divergent Agonist-Dependent Antagonism |
|
|
395 | (1) |
|
|
|
396 | (1) |
|
|
|
396 | (1) |
|
|
|
397 | (5) |
|
|
|
397 | (2) |
|
14.6.2 Drug-Drug Interactions |
|
|
399 | (1) |
|
|
|
399 | (1) |
|
|
|
399 | (1) |
|
|
|
399 | (1) |
|
|
|
400 | (1) |
|
|
|
400 | (1) |
|
|
|
400 | (1) |
|
14.6.9 Renal Clearance II |
|
|
400 | (1) |
|
14.6.10 Renal Clearance III |
|
|
401 | (1) |
|
|
|
401 | (1) |
|
14.6.12 Predictive Pharmacokinetics I |
|
|
401 | (1) |
|
14.6.13 Predictive Pharmacokinetics II |
|
|
401 | (1) |
|
14.6.14 Predictive Pharmacokinetics III |
|
|
401 | (1) |
|
14.6.15 Log D and Pharmacokinetics |
|
|
401 | (1) |
|
|
|
402 | (1) |
|
|
|
402 | (1) |
|
|
|
403 | (12) |
|
A.1 Statistical Tables of Use for Assessing Significant Difference |
|
|
403 | (8) |
|
A.2 Mathematical Fitting Functions |
|
|
411 | (4) |
| Glossary of Pharmacological Terms |
|
415 | (6) |
| Index |
|
421 | |