Molecular Mechanisms Of Drug Action

310 Pages·1994·17.389 MB·English

by  Christopher J. Coulson

Molecular mechanisms of
drug action

Molecular mechanisms of
drug action
Second Edition
Christopher J. Coulson
Glaxo Group Research, UK
UK Taylor & Francis Ltd, 4 John St., London WCIN 2ET
USA Taylor & Francis Inc., 1900 Frost Road, Suite 101, Bristol, PA 19007
Copyright 0 Taylor & Francis Ltd 1994
All rights reserved. No part of this publication may be reproduced,
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the prior permission of the copyright owner.
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British
Library.
ISBN 0-7484-0068-O (cloth)
ISBN o-7484-0078-8 (paper)
Library of Congress Cataloging-in-Publication Data are available
Cover design by Russell Beach
Typeset by Photo.Graphics
Printed in Great Britain by Burgess Science Press, Basingstoke, on
paper which has a specified pH value on final manufacture of not
less than 7.5 and is therefore @acid free’.
Contents
Preface
Preface to second edition
Glossary
1. General principles 1
1.1 Background 1
1.2 Do drugs have a specific mode of action? 1
1.3 Basic processes 2
1.4 Drug binding to enzymes 3
1.5 Drug binding to receptors 5
1.6 Further considerations 6
1.7 Partition coefficient 7
1.8 Drug nomenclature 8
1.9 Stereochemistry 9
1.10 The future 11
References 11
2. Nucleic acid biosynthesis and catabolism 13
2.1 Introduction 13
2.1.1 Overall scheme 15
2.2 Nucleotide biosyntheses - enzyme targets of drugs 18
2.2.1 Dihydroorotate dehydrogenase - actovaquone as
antimalarial 18
2.2.2 Dihydropteroate synthetase - sulphonamides as anti-
bacterials 19
2.2.3 Dihydrofolate reductase - trimethoprim and
pyrimethamine as anti-bacterials, methotrexate as
anti-cancer 21
2.2.4 Ribonucleotide reductase - hydroxyurea as anti-cancer 23
2.2.5 Thymidylate synthetase - 5-fluorouracil as anti-cancer,
5-fluorocytosine as antifungal 25
V
vi Molecular mechanisms of drug action
2.2.6 Inosine monophosphate dehydrogenase - ribavirin as
anti-viral 26
2.3 DNA biosynthesis 28
2.3.1 Herpesvirus DNA polymerase - acyclovir and
vidarabine as anti-virals 30
2.3.2 Mammalian DNA polymerase - cytarabine as anti-
leukaemic 32
2.3.3 DNA topoisomerases 33
2.3.4 Reverse transcriptase - azidothymidine ror AIDS 38
2.3.5 Bacterial RNA polymerase - rifampicin as
antimycobacterial 40
2.4 Nucleotide catabolism 40
2.4.1 Adenosine deaminase - 2deoxycoformycin as anti-
leukaemic 41
2.4.2 Xanthine oxidase - allopurinol for gout 43
2.4.3 Guanylate cyclase 45
Questions 46
References 47
3. Protein biosynthesis 51
3.1 Introduction 51
3.2 Aminoglycosides 54
3.3 Chloramphenicol 57
3.4 Tetracyclines 59
3.5 Erythromycin 60
3.6 Clindamycin 61
Questions 62
References 63
4. Carbohydrate metabolism 65
4.1 Introduction 65
4.2 Metronidazole action - anaerobic protozoa1 and bacterial
infections 66
4.3 Medical use of metronidazole 69
4.4 a-Glucosidase inhibitors - acarbose as antidiabetic 70
4.5 Sialidase inhibitor-4-guanidino-NeuSAcZen for influenza 71
Questions 72
References 72
5. Cell wall biosynthesis 75
5.1 Introduction 75
5.2 Plactams 77
5.2.1 Penicillin-binding proteins 78
Contents vii
5.2.2 PIactamases 81
5.2.3 PLactam therapy 84
5.3 Vancomycin 86
5.4 Mycolic acid synthesis - isoniazid for tuberculosis 88
5.5 PGlucan synthetase 90
Questions 90
References 91
6. Steroid biosynthesis and action 95
6.1 Introduction 95
6.2 Sterol biosynthesis 100
6.2.1 PHydroxy-pmethylglutaryl CoA reductase - lovastatin
as hypocholesterolaemic 100
6.2.2 Squalene epoxidase - naftitine as antifungal 103
6.2.3 Lanosterol demethylation - ketoconazole as antifungal 104
6.3 Steroid biosynthesis 107
6.3.1 Steroid 17,20-lyase - ketoconazole for steroid-
dependent tumours 107
6.3.2 11 PSteroid hydroxylase - metyrapone for
hypercortisolism 108
6.3.3 Aromatase - aminoghttethimide for hormone-
dependent cancers 109
6.3.4 So-Reductase 110
6.4 Steroid receptor ligands 111
6.4.1 Oestrogen/progesterone receptor agonists - oral
contraceptives 111
6.4.2 Oestrogen antagonists - tamoxifen for oestrogen-
dependent cancer, clomiphene to stimulate
ovulation 114
6.43 Progesterone antagonist - mifepristone as abortifacient 116
6.4.4 Androgen antagonist 116
6.4.5 AIdosterone antagonist - spironolactone as diuretic 117
Questions 119
References 120
7. Prostaglandin and leukotriene biosynthesis and
123
ZWtiOll
7.1 Introduction 123
7.2 Phospholipase inhibition - glucocorticoids for asthma and
arthritis 124
7.3 Prostaglandin synthetase inhibitors - aspirin and other non-
steroidal anti-inflammatories 127
7.4 Rheumatoid arthritis 130
7.5 Thromboxane synthesis 132
Vll..la Molecular mechanisms of drug action
7.6 Leukotriene biosynthesis 132
Questions 133
References 133
8. Zinc metalloenzymes 135
8.1 Introduction 135
8.2 Carbonic anhydrase - methazolamide for glaucoma 136
8.3 Angiotensin-converting enzyme 141
8.3.1 Angiotensin-converting enzyme inhibitors - captopril
and enalapril for hypertension 145
8.3.2 Pharmacology of ACE inhibitors 146
8.4 Endopeptidase 24.11 - thiorphan as analgesic 148
Questions 149
References 150
9. Neurotransmitter action and metabolism 151
9.1 Introduction 151
9.1.1 G-Protein linked receptor structure 154
9.1.2 Signal transduction and receptor occupancy 155
9.1.3 Drug development 159
9.2 Adrenergic receptors 160
9.2.1 cu-Adrenergic receptors 161
9.2.2 PAdrenergic receptors 163
9.2.3 Mixed cr- and @unagonist 166
9.3 Dopamine receptors 166
9.3.1 Dopamine agonists - L-dopa and bromocryptine for
Parkinsonism, fenoldapam for hypertension 167
9.3‘2 Dopamine antagonists - phenothiazines,
butyrophenones and diphenylbutylpiperidines for
schizophrenia 169
9.4 Serotonin receptors 174
9.4.1 5HT,, receptors, anxiety and depression 175
9.4.2 5HT,, receptors and migraine 176
9.4.3 5HT, receptors 178
9.4.4 5HT, receptors 178
9.5 Serotonin and noradrenaline re-uptake mechanisms - tricyclic
anti-depressants 180
9.6 Monoamine oxidase - tranylcypromine and moclobemide for
depression, deprenyl for Parklnsonism 183
9.6.1 Monoamine oxidase and Parkinsonism 187
9.7 Acetylcholine action 188
9.7.1 Muscarinic receptor - pirenzepin for ulcers, atropine
pre-anaesthetic medication, pilocarpine for
glaucoma 189
Contents ix
9.7.2 Acetylcholinesterase - pyridostigmine for myasthenia
gravis 192
9.8 4Aminobutyric acid receptor - benzodiazepines as hypnotics,
avermectin as anthehninthic, baclofen for spastic@ 194
9.8.1 Benzodiazepines 195
9.8.2 Avermectin 197
9.8.3 Baclofen 200
9.9 Opiate receptors - morphine for pain 201
9.9.1 Opioid dependence 204
9.92 Pentazocine as analgesic 204
9.9.3 Loperamide as anti-diarrhoea1 205
9.10 Histamine receptors - mepyramine as anti-allergic, cimetidine
as anti-ulcer 206
9.10.1 H, receptor antagonists 207
9.10.2 H, receptor antagonists 208
Questions 210
References 210
10. Membrane-active agents 215
10.1 Introduction 215
10.1.1 Membrane structure 215
10.1.2 Dynamics of the heart beat 217
10.2 The sodium channel 219
10.2.1 Sodium channel blockers - procaine as a local
anaesthetic 220
10.2.2 Anti-arrhythmic agents - lidocaine as an anti-
arrhythmic 222
10.2.3 Diuretics - amiloride and triamterene 223
10.3 The calcium channel 225
10.3.1 Calcium channel antagonists - verapamil, nifedipine
for hypertension and heart failure 227
10.4 Coupled sodium-chloride ion channels - furosemide and
ethacrynic acid as diuretics 230
10.5 Membrane-bound ATPases 231
10.5.1 Sodium-potassium-ATPase - cardiac glycosides for
heart failure 232
10.5.2 Potassium-hydrogen-ATPase - omeprazole for ulcers 236
10.6 CromogIycate - calcium antagonist or membrane stabilizer? 239
10.6.1 Cromoglycate action 239
10.7 Cyclosporin 241
10.8 Potassium channel opening 243
10.9 Sterol Iigands - polyene antibiotics 244
10.9.1 Amphotericin action 245
Questions 247
References 248
Molecular mechanisms of drug action
X
11. Mlcrotubule assembly 251
11.1 Introduction 251
11.2 Colchicine for gout 252
11.3 Vinca alkaloids as anti-tumour agents 255
11.4 Griseofulvin as an antifungal agent 256
11.5 Benzimidazoles as anthehninthics 257
11.6 Tax01 as an anti-tumour agent 259
Questions 260
References 260
12. Hormonalmodulators 261
12.1 Introduction 261
12.2 Diabetes mellitus 261
12.2.1 The action of insulin 262
12.2.2 Insulin therapy 264
12.3 Sulphonylureas as hypoglycaemic agents 266
12.4 Gonadotrophin-hormone-releasing hormone (GnRH) analogues 268
Questions 273
References 273
Appendix: Quantifkationoflipd-ma~omole~ebhdhg 275
A.1 Enzyme kinetics: I,, or Ki? 275
A.2 Drug binding to receptors 278
A.3 Ligand-protein binding 280
References 282
285
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