UNIVERSITÀ DI PISA
SCUOLA DI DOTTORATO DI RICERCA IN
“SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE”
Dottorato di Ricerca in
“Scienze del Farmaco e delle Sostanze Bioattive”
XIX CICLO (2004-2006)
“
Design and synthesis
of new potential BK-openers”
CANDIDATO: Francesca Lidia Fiamingo
TUTOR: Oreste Livi
DIRETTORE DELLA SCUOLA (Prof.ssa Claudia Martini)
Index
Chapter 1
1.1 Ion channels: general properties pag. 1
1.2 Potassium channels: classification 9
1.3 The Standardized K Channel Nomenclature 10
1.4 Voltage-gated K channels 13
1.5 Two transmembrane one-pore channels 13
1.6 Four transmembrane two-pore channels 14
1.7 Human Gene Nomenclature Committee System 15
1.8 Concluding remarks 19
Chapter 2 2.1 Potassium channels: from the Crystal Structure to a Nobel Prize pag. 22 2.2 The first crystal structure 22
2.3 Concluding remarks 29
Chapter 3 3.1 Potassium Channels as Therapeutic Drug Targets pag. 31 3.2 Potassium channels as universal regulators of cellular function 31
3.3 The role of potassium channels in vascular smooth muscle cells 33
3.4 The role of potassium channels in vascular endothelial cells 34
Chapter 4
4.1Calcium-activated Potassium Channel pag. 41 4.2 Small-conductance Calcium Dependent Potassium
Channels (SK) 41
4.3 SK channels, apamin and pathophysiological processes 44
4.4 Intermediate conductance calcium-activated potassium channels (IK) 44
4.5 Large-conductance potassium channels 45
Chapter 5 5.1 Structure of BK Channels pag. 41 5.2 The β-subunits 50
5.3 Physiological role of βsubunits 52
5.4 Tissue distribution 52
Chapter 6 6.1 Pharmacology of BK Channels pag. 58 6.2 Cardiovascular system 58 6.3. Urinary system 60 6.4 Nervous system 61 6.4 Broncho-Tracheal system 63 Chapter 7 7.1 BK as drug target pag. 66 7.1.1 Introduction 66
7.1.3 Section II 76
7.2 Discussion 79
7.3 New Pharmacophoric Model 86
7.4 Appendix 98
Chapter 8 8.1 Objectives of doctorate pag. 99 8.2 Concludig remarks 101
Chapter 9 9. Heterocyclic analogs of benzanilide derivatives as potassium channel activators. IX 103
Chapter 10 10.Structural modification of benzanilide derivatives effective potassium channel openers.X 139
Chapter 11 11. New amido derivatives as potential BKca potassium channel activators XI 145
Chapter 12 12. 1,2,3-Triazol-carboxanilides and 1,2,3-(N-benzyl)-carboxamides as BK-potassium channel activators. XII 161
Chapter 13 13.1 QSAR study on BK channel activators 181
13.1.1 Introduction 182
13.2 Methods 182 13.2.1 Dataset collection and preliminary
handling of the molecules 182
13.2.2 Rational division of the dataset into training and test sets 183
13.2.3 QSAR and Molecular Descriptors 183
13.2.4 Statistical Analysis for model validation 184
13.3 Results and Discussion 185
