synthesis and in vitro pharmacology of a series of histamine h2 ...

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Chapter 2 Figure 4: Non-identical twin drugs clofibric acid nicotinic acid 2.2.C Symmetrical twin drugs Symmetrical twin drugs, also called "Siamese twins", contain two identical structural moieties (fig. 5). After administration these compounds, however, remain intact. In bifunctional symmetrical drugs, the two identical pharmacophore groups can be directly linked to each other or via a spacer. The examples shown in figure 5 are the anticoagulant dicoumarol, the analgesic forbisen and the a-adrenoceptor blocker dibozane. H,C. H 3C- N N Figure 5: Symmetrical drugs ("Siamese twins") Many symmetrical ligands have been used to identify the interbinding site distances at pharmacological receptors. In these drugs the affinity for the receptors might be enhanced by dimeric agents which are capable of successfully bridging two adjacent receptors. 36
Chapter 2 Dimeric 1,4-dihydropyridine (DHP) calcium channel blockers have been synthesized and pharmacologically evaluated in a radioligand binding assay 2 . The alkylene spacer linking the two identical DHP derivatives was varied from an ethyl to a dodecyl chain (fig. 6). However, the affinities of the dimeric compounds were similar to that of the corresponding monomelic DHPs. Inactivation, by proper structural changes, of one of the DHP structural moieties revealed that this series of ligands did not bridge adjacent 1,4-DHP receptors of the calcium channel. H H Figure 6: Dimeric 1,4-dihydropyridines; n varies from 2,4,6,8,10 to 12 2.3 Pseudo-hybrids Pseudo-hybrids are drugs which combine two or more pharmacological actions in a racemic mixture of a chiral molecule. Many chiral adrenoceptor ligands, tested as racemates exhibit more than one pharmacological action. However, separation of the stereoisomers often revealed that the pharmacophoric groups are localized in the different stereoisomers 3 . Labetalol (AH-5158) is the best known example of a pseudohybrid molecule. Labetalol contains two chiral centers and therefore consists of four stereoisomers (fig.7). Racemic labetalol exhibits oc r, p r and p2-adrenergic blocking activities. In table 1 the adrenoceptor blocking activities of racemic labetalol and its enantiomers are given. Figure 7: Racemic labetalol (* indicates chiral center) Table 1 shows that, although the racemic labetalol is a potent antagonist for all three receptors, the oci-adrenergic blocking activity mainly resides in the (S,R) isomer, while (3-adrenergic blocking activity is found in the (R,R) isomer called dilevalol. Therefore, labetalol is considered to be a pseudo-hybrid molecule. 37
Page 1 and 2: SYNTHESIS AND IN VITRO PHARMACOLOGY
Page 3 and 4: Promotor : prof.dr H. Timmerman Cop
Page 5 and 6: The investigations described in thi
Page 7 and 8: Chapter 1 Chapter 1 Pharmacotherape
Page 9 and 10: Chapter 1 2.2 Role of calcium Calci
Page 11 and 12: Chapter 1 The excitation-contractio
Page 13 and 14: Chapter 1 Antiarrhythmic drugs modi
Page 15 and 16: Chapter 1 Until now, no selective c
Page 17 and 18: Chapter 1 pyridines are expected to
Page 19 and 20: Chapter 1 Like the p-adrenoceptor s
Page 21 and 22: Chapter 1 3.3.3 Phosphodiesterase I
Page 23 and 24: arteries brain Central Nervous Syst
Page 25 and 26: Chapter 1 The development of renin
Page 27 and 28: ^-ADRENOCEPTOR ANTAGONISTS Chapter
Page 29 and 30: 51 Cromakalim 52 Nicorandil 53 Pina
Page 31 and 32: Chapter 1 The CCBs are a heterogene
Page 33 and 34: Chapter 1 4.2 Combination of cardio
Page 35 and 36: Chapter 1 22 Claremon DA, Baldwin J
Page 37 and 38: Chapter 1 56 Carini DJ, Chiu AT, Du
Page 39 and 40: Chapter 2 Chapter 2 Hybrid molecule
Page 41: identical twin drug (A-A) - 2A non-
Page 45 and 46: Chapter 2 plasma-protein binding si
Page 47 and 48: Chapter 2 PAF antagonist, showing o
Page 49 and 50: Corsano et al. 18 Chapter 2 have sy
Page 51 and 52: Chapter 2 Görlitzer et al. 21 synt
Page 53 and 54: Chapter 2 enzyme cyclooxygenase is
Page 55 and 56: Chapter 2 Table 4: TxA 2/PGH 2 bind
Page 57 and 58: Chapter 2 the compound had poor ora
Page 59 and 60: Chapter 2 presented to explain why
Page 61 and 62: Chapter! When two antihypertensive
Page 63 and 64: Chapter 2 Table 9: p-Receptor affin
Page 65 and 66: Chapter 2 dual vasodilating mechani
Page 67 and 68: Figure 33: Hybrid molecule DG20 (R
Page 69 and 70: 5.4 Antihypertensive hybrid molecul
Page 71 and 72: Chapter 2 However, due to the terat
Page 73 and 74: Figure 43: Hybrid molecule possessi
Page 75 and 76: Chapter 2 5.4.e Hybrid molecules co
Page 77 and 78: Chapter 2 The two pairs of enantiom
Page 79 and 80: I H CH 3 Figure 50: Urapidil, an 04
Page 81 and 82: Chapter 2 15 Pilar Ortega M, Del Ca
Page 83 and 84: Chapter 2 AI Morgan TK Jr, Lis R, L
Page 85 and 86: Chapter 2 68 Baldwin JJ, Lurama WC
Page 87 and 88: Chapter 3 '2 Chapter 3 Organic nitr
Page 89 and 90: Chapter 3 phosphorylation of contra
Page 91 and 92: Chapter 3 In table 1, the in vitro
Page 93 and 94:
Figure 8: Ligands for the histamine
Page 95 and 96:
Chapter 3 Nitrate esters can be obt
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Chapter 3 resulting in the loss of
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Chapter 3 14 Yeates RA, Possible me
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Chapter 4 Chapter 4 2 + L-type volt
Page 103 and 104:
Chapter 4 homologous domains surrou
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Chapter 4 channel, which is suggest
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Chapter 4 channel blocking activity
Page 109 and 110:
Chapter 4 Structural modifications
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Chapter 4 Table 6: Calcium channel
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RiOOC COORo compound R\ R 2 nicardi
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Chapter 4 enantiomer.(-)-S11568 inh
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Chapter 4 The cardiovascular activi
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Chapter 4 rat tail artery 73 . Also
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Chapter 4 The compound HOE 166 18 (
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Figure 11: Molecular structure of a
Page 125 and 126:
Chapter 4 SM-6586 was a more potent
Page 127 and 128:
Chapter 4 inactivated (resting) sta
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Chapter 4 20 van Amsterdam F.T.M, Z
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Chapter 4 45 Muto K, Kuroda T, Kawa
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Chapter 4 67 Gaviraghi G, Lacidipin
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Chapter 4 95 Goldmann S, Stoltefuß
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Chapter 5 Synthesis and in vitro ph
Page 139 and 140:
Chapters
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Chapters from the 1,4-DHPs 17. In t
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3 Pharmacology Chapter 5 3.1 In vit
Page 145 and 146:
Chapter 5 Table II. Calcium blockin
Page 147 and 148:
Chapter 5 Radioligand binding affin
Page 149 and 150:
Chapters 13.1 Hz, 2H, pyridine-CHb-
Page 151 and 152:
2-(2-aminoethylthio)methyl-3,5-dica
Page 153 and 154:
Chapters 5 Katz AM, In: Calcium ant
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Chapter 6 Synthesis and in vitro ph
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Chapter 6 by nifedipine analogues i
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Chapter 6 4 Results and discussion
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lipid compartment protein compartme
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Chapter 6 phthalimide-H), 7.77-7.80
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Chapter 6 ^-NMR (CDCI3): 1.18 ppm (
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Chapter 6 *H-NMR (DMSO-d6): 1.07 pp
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Chapter 7 Chapter 7 Synthesis and i
Page 171 and 172:
5 Impromidine R 2 9 Arpromidine R 1
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Chapter 7 generation calcium channe
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3.2 In vitro histamine Ho-agonistic
Page 177 and 178:
Chapter 7 As reported previously in
Page 179 and 180:
Chapter 7 Table III: Relative calci
Page 181 and 182:
Chapter 7 Figure 4 nicely demonstra
Page 183 and 184:
Chapter 7 blocking activities are c
Page 185 and 186:
Chapter 7 4.4 Histamine H ragonisti
Page 187 and 188:
Chapter 7 chronotropic activity in
Page 189 and 190:
Chapter 7 N-benzoyl-N'-{3-{[3,5-die
Page 191 and 192:
Chapter 7 phenyl-// 5), 7.63-7.67 p
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Chapter 7 and N-C-C-C// 2-imidazole
Page 195 and 196:
Chapter 7 (s, 1H, pyridine-// 4), 6
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Chapter 8 Chapter 8 A new series of
Page 199 and 200:
Chapter 8 structural moiety of impr
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Chapter 8 All compounds except VUF
Page 203 and 204:
4 Pharmacology Chapter 8 4.1 Histam
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Chapter 8 of the 3,3-diphenylpropyl
Page 207 and 208:
Chapter 8 Based on the observations
Page 209 and 210:
Chapter 8 iH-NMR (CDCI3): 1.28-1.50
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Chapter 8 13 Vitali T, Impicciatore
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Summary The investigations describe
Page 215 and 216:
Samenvatting Het in dit proefschrif
Page 217 and 218:
substituenten, zoals een difenylalk
Page 219 and 220:
Curriculum Vitae Johannes Antonius
Page 221:
voor de prettige sociale contacten
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