Potassium Channels And Their Modulators From Synthesis To Clinical Experience

Book Cover......Page 1
Half-Title......Page 2
Title......Page 5
Copyright......Page 6
Contents......Page 7
Contributors......Page 9
Foreword......Page 11
Preface......Page 14
1.1  Introduction......Page 16
1.2  General Synthetic Aspects—Racemic Derivatives......Page 17
1.3  Preparation of Enantiomers......Page 25
1.4  Benzopyran KCAs with Modified Aromatic Ring......Page 27
1.5  Benzopyran KCAs with Modified Pyran Ring......Page 29
1.6.1  C-3 Ketone Derivatives and Aromatic SN2’ Substitution......Page 32
1.6.2  Michael-type Addition at C-3......Page 35
1.6.3  Reactions of Benzopyranols with DAST......Page 36
1.6.4  C-3 Carbon and Nitrogen Linked Moieties......Page 37
1.6.5  Reactions of C-4 Pyrrole Derivatives......Page 39
References......Page 41
Additional References......Page 45
2.1  Introduction......Page 47
2.2  Stereochemistry in the Benzopyran Series......Page 48
Lactams and other α-carbonyl containing replacements......Page 51
Lactam replacements lacking α-carbonyl groups......Page 57
2.3.2  Position 3......Page 65
2.3.3  Position 2......Page 67
2.4.1  Replacement of the Pyran Ring......Page 70
2.4.2  Replacement of the Aromatic Segment......Page 72
2.5  Aromatic Substitution......Page 74
2.6  Conclusions......Page 75
References......Page 76
Recent Literature......Page 79
3.1  Introduction......Page 81
The discovery of aprikalim......Page 82
KCA potency of aprikalim and close analogues......Page 84
3.2.2  Structural Modification of Aprikalim......Page 85
Modification of the thioformamide group......Page 86
Summary of SARs......Page 87
3.2.2  Cyclohexanone Analogues......Page 88
Alkene and alkane analogues......Page 90
Sulfonamide analogues......Page 91
Oxime, hydroxylamine and amine analogues......Page 92
Ester analogues......Page 93
3.2.3  Other Syntheses and Hybrid Structures......Page 94
Discovery and initial SAR studies......Page 95
KCA activity of pinacidil analogues......Page 96
Stereochemistry and molecular modeling of pinacidil analogues......Page 97
Aminopyridine analogues......Page 98
3.3.3  Hybrid Analogues......Page 99
3.4.1  Nicorandil......Page 100
3.5.1  Anilide Tertiary Carbinols......Page 101
3.6  Conclusion......Page 102
References......Page 103
Recent Literature......Page 104
4.1.1  Structure......Page 106
4.1.2  Rotation of the 4-pyrrolidinone in Cromakalim......Page 107
4.1.3  Flipping the Pyran Ring......Page 123
4.7.4  Stereochemistry......Page 127
4.2.2  Replacements for the Benzene Ring......Page 129
4.3  Pyrrolidinone Replacements......Page 130
4.3.7  Cyclic Replacements......Page 131
4.3.2  Acyclic Replacements......Page 132
4.4  The Aprikalim Series......Page 134
4.4.1  Structure of Aprikalim......Page 135
4.5  Studies on Pinacidil......Page 137
4.5.2  Rotation of the N- and N’-substituents of Pinacidil......Page 138
4.6  Possible Pharmacophore Models......Page 139
References......Page 140
Recent Literature......Page 142
5.1  Introduction......Page 143
5.2.2  Sulphonylureas and Related Molecules......Page 144
5.2.3  Imidazolines and Related Molecules......Page 149
LinoglirideLinogliride is a member of a class of guanidine-based insulin secretogogues (Mohrbacher et al., 1987) and has some structural similarities with the imidazolines. It is unclear as yet if this similarity is of consequence in its interaction with a receptor or if linogliride has the same mode of action as the sulphonylureas. Nevertheless, linogliride has been shown electrophysiologically to inhibit KATP channels in pancreatic β-cells, an effect which is sensitive to pre-treatment with tol......Page 150
Ciclazindol......Page 151
5.3.1  Introduction......Page 152
5.3.2  Quaternary Compounds......Page 155
First generation analogues......Page 157
Second generation analogues......Page 158
5.3.3  Combined Class III Pharmacophore......Page 161
5.3.4  Miscellaneous Class III Agents......Page 162
5.4  Aminopyridines......Page 163
5.6  Conclusions......Page 165
References......Page 166
6.1  Introduction......Page 171
6.2.1  K Channels Belonging to the S4 Channel Superfamily (Jan and Jan, 1990a)......Page 172
6.2.2  Channels with Monomers Containing Two Membrane Spanning Regions......Page 174
6.3  Origin of Diversity in K Channels Belonging to the S4 Superfamily......Page 175
Drosophila......Page 176
Mammals......Page 179
6.3.2  Multiple Genes......Page 181
6.3.3  Formation of Heteromultimeric Channels is Fundamental in Subunit Composition and Diversity of K Channels......Page 185
6.4  Structural Determinants for K Channel Assembly......Page 186
6.5  K Channels are Tetramers......Page 188
6.6  Differential Expression of K Channels......Page 189
6.6.1  Differential K Channel Expression is a General Phenomenon......Page 190
6.6.2  Heteromultimeric Channels in vivo......Page 198
6.6.3  Regulation of K Channel Expression......Page 199
6.7  Conclusion......Page 200
References......Page 201
Some K channels appear to be dimers......Page 207
Additional References......Page 208
7.2  Structural Division of K Channels Deduced from Molecular Biology......Page 209
7.2.1  Vascular Smooth Muscle Representatives of these Families......Page 210
7.3  K Channels in Vascular Smooth Muscle Cells: Electrophysiological Overview......Page 211
7.3.1   Ca-activated K Channels......Page 212
7.3.3  KATP Channels and Inward Rectifier Channels in Vascular Smooth Muscle......Page 213
Regulation by ATP of KATP channels......Page 214
Other intracellular modulators of  KATP......Page 215
7.4  Are Vascular KATP Channels Open under Basal Conditions?......Page 218
7.4.1  KATP Channel-independent Effects of Glibenclamide......Page 219
7.4.2  Agonist Mediated Modulation......Page 221
7.5.1  The K Channel Opened by KCOs......Page 222
7.5.2  Other Actions of KCOs......Page 223
References......Page 225
8.1  Introduction......Page 229
8.2  Natural and Synthetic Activators of Vascular KATP Channels......Page 231
8.3  Binding Studies with KATP Channel Activators in Vascular Smooth Muscle......Page 232
Type of K Channel activated by the KCAs......Page 233
Mechanisms of K channel opening......Page 234
8.4.2  Electrophysiological and Tracer Efflux Studies......Page 235
Glibenclamide......Page 236
Other sulphonylureas and related insulinotropes......Page 239
Other blockers  Symmetrical tetra-n-alkylammonium ions......Page 243
Blockers that inhibit KCA-induced channel opening more than vasorelaxation......Page 244
8.5  Vasorelaxant Properties of the KATP Channel Activators......Page 245
8.6  Mechanism of KATP Channel Activator-induced Vasorelaxation......Page 248
8.7  BKCa Channel Activators......Page 249
References......Page 251
9.2  Acute Blood Pressure Studies......Page 257
9.4  Heart Rate and Plasma Renin Activity......Page 260
9.5  The Venous System......Page 261
9.6.1  The Cerebral Circulation......Page 262
9.6.2  Coronary Circulation......Page 264
9.6.3  Splanchnic Circulation......Page 266
9.6.4  Renal Circulation......Page 267
9.6.5  Skeletal Muscle Circulation......Page 272
9.6.6  Pulmonary Circulation......Page 273
9.7  Microcirculation......Page 275
9.8.1  Glibenclamide......Page 277
9.8.4  Effect of KCAs on Stimulation of Exogenous and Endogenous Receptors......Page 280
9.9  Conclusion......Page 281
References......Page 282
Recent Literature......Page 285
10.1  Introduction......Page 288
10.2.1  Automaticity......Page 290
10.2.3  Reentry......Page 291
10.3  Cardiac K Channels......Page 292
10.4  K Channel Blockers......Page 293
Multiple types of IK channels......Page 294
Specific lKr blockers......Page 299
Nonspecific blockers of lK......Page 303
Properties and pharmacological modulation of delayed rectifier K channels expressed in heterologous systems......Page 305
10.4.2  Inward Rectifier K Channel Blockers......Page 307
10.4.3  Transient Outward K Channel Blockers......Page 308
10.4.5  IK(Na) Blockers......Page 312
10.5  Rate-dependent Effects of K Channel Blockers......Page 313
10.6  Modulators of IK(ATP)......Page 315
10.6.1  IK(ATP) Blockers......Page 318
10.6.2  K(ATP) Activators......Page 320
References......Page 324
11.1  Introduction......Page 331
11.2  Evidence for an Endogenous Cardioprotective Role of the KATP Channel—The Preconditioning Phenomenon......Page 332
11.3  Effects of KCAs and KCBs in the Ischemic Myocardium......Page 334
11.3.1  In Vitro Models......Page 335
11.3.2  In Vivo Models—Stunned Myocardium......Page 337
11.3.3  In Vivo Models—Myocardial Infarction......Page 343
11.4  Evidence for a Cardioprotective Effect of KCAs in Other Models......Page 345
References......Page 347
12.1.1  Asthma Therapy......Page 351
12.1.2  The Potential of Potassium Channel Activators......Page 353
12.1.3  KCAs that have been Evaluated for Bronchodilator Activity......Page 354
12.2  Airways Smooth Muscle Relaxation in Vitro......Page 356
12.2.1  Cholinergic Tone......Page 357
12.2.2  Histaminergic Tone......Page 358
12.2.3  Airway Selectivity......Page 359
12.3  Airways Smooth Muscle Relaxation in Vivo......Page 361
12.3.2  Cholinergic Challenge......Page 362
12.3.3  Airway Selectivity......Page 363
12.3.4  Inhaled Administration......Page 365
12.4  Neural Effects......Page 367
12.5  Hyperresponsiveness—Contribution of Anti-inflammatory and Neural Inhibitory Activity......Page 369
12.6.1  Evidence that K Channels are Opened by KCAs......Page 371
12.6.2  Intracellular Events......Page 374
12.7  Conclusions and Outlook......Page 376
References......Page 377
Recent Literature......Page 382
13.1  Introduction......Page 384
13.2  Ca Channels and Insulin-secreting Cells......Page 387
13.3.1  KATP Channels......Page 388
Role of KATP channels in β-cell electrophysiology......Page 389
Regulation of KATP channels in β-cells......Page 390
Pharmacology of KATP channels in β-cells......Page 397
Activators of KATP channels......Page 401
13.3.2  Ca and Voltage-Gated K (KCa) Channels......Page 407
13.3.4  Non-selective Cation Channels......Page 410
13.4  Na Channels and Insulin-secreting Cells......Page 411
References......Page 413
14.2.1  Ureters......Page 421
K channels in ureter......Page 422
14.2.2  Detrusor......Page 424
K channels in the detrusor: contribution to shape of action potential......Page 427
Effects of K-channel opening drugs on detrusor......Page 429
Mechanisms of action of the KCOs on detrusor......Page 430
Clinical potential......Page 435
14.2.3  Urethra......Page 436
K channels in urethra......Page 437
14.3.1  Uterus......Page 440
K channels in rat uterus......Page 442
14.4  Male Genital Tract Smooth Muscles......Page 444
References......Page 445
Recent Literature......Page 448
15.1  Introduction......Page 449
15.2  Endogenous Modulators of CNS K Channels......Page 451
15.3  Toxin Modulators of CNS K Channels......Page 452
15.3.2  Bee Venom Toxins......Page 453
15.4  Drugs Modulating CNS K Channels......Page 454
15.4.1  KATP Channel Modulators......Page 455
15.5.1  Potassium Channel Blockers......Page 459
Substantia Nigra......Page 460
Hippocampus......Page 461
Other brain areas......Page 462
15.6.1  Ischaemic Stroke......Page 463
15.6.2  Epilepsy......Page 464
15.6.5  Alzheimer’s Disease......Page 466
15.7  Summary and Conclusions......Page 467
References......Page 468
Recent Literature......Page 473
16.1  KCAs......Page 475
16.2  Therapeutic Potential......Page 476
16.3.1  Hypertension......Page 477
16.3.2  Asthma......Page 483
16.3.3  Urinary Incontinence......Page 486
16.4  Future Prospects for KCAs......Page 487
16.5  KCBs......Page 490
16.6  Amiodarone......Page 491
16.7  Sotalol......Page 492
16.9  Dofetilide......Page 494
16.11  Almokalant......Page 496
16.12  Ibutilide......Page 497
16.14  Reverse Use-dependence......Page 498
16.15  Proarrhythmia......Page 500
16.16  Summary and Future Directions......Page 501
References......Page 503
Recent Literature......Page 508
Abbreviations......Page 509
Index of Compounds......Page 514
Index......Page 518