MEDICINALE CHEMIE
1. INHOUDSOPGAVE
2. Acetylcholine & de cholinerge receptoren ............................................... 7
A. inleiding............................................................................................. 7
1. Autonoom ZS ........................................................................................................ 8
1.1. Sympatisch ZS ................................................................................................ 8
1.2. Parasympatisch ZS ........................................................................................... 9
B. het neurotransmissieproces ................................................................... 12
C. de nicotinereceptor ............................................................................. 15
D. De muscarinereceptor .......................................................................... 19
1. M1-receptor ........................................................................................................ 21
2. M2-receptor ........................................................................................................ 23
3. M3-receptor ........................................................................................................ 23
E. structuur van acetylcholine ...................................................................... 24
F. SAR ..................................................................................................... 26
1. De nicotinereceptor .............................................................................................. 26
3.1. agonisten .................................................................................................... 26
3.2. antagonisten ................................................................................................ 30
3.2.1 ganglionblokkers ..................................................................................... 30
3.2.2 neuromusculaire blokkers (curares) ............................................................... 31
3.2.3 lokale anesthetica ................................................................................... 35
2. de muscarinereceptor ............................................................................................ 40
2.1 agonisten .................................................................................................... 40
2.2 antagonisten ................................................................................................ 45
2.2.1 solanaceae alkaloïden & synthetische analogen ................................................. 46
2.2.2 analogen met gewijzigde tropaanring............................................................. 48
2.2.3 analogen zonder esterfunctie ...................................................................... 49
2.2.4 andere muscarine antagonisten .................................................................... 50
G. biologische activiteit & therapeutisch gebruik van cholinerge agonisten ........... 51
1 Nicotine-agonisten ................................................................................................ 51
2 Nicotine-antagonisten ............................................................................................ 52
2.1 ganglionblokkers ............................................................................................ 52
2.2 neuromusculaire blokkers ................................................................................. 52
3 Muscarine-agonisten .............................................................................................. 53
4 Muscarine-antagonisten .......................................................................................... 54
H. acetylcholinesteraseremmers ................................................................. 56
1 reversibele, competitieve enzyminhibitoren .................................................................. 57
2 inhibitoren die een covalente binding vormen met de katalytische plaats van het
acetylcholinesterase (irreversibele inhibitoren) .................................................................... 58
3. (NOR)adrenaline & de adrenerge receptoren ........................................... 64
A. de adrenerge neurotransmissie ............................................................... 64
B. structuur van adrenaline: stereochemie & conformatie ................................ 73
C. 𝜶-adrenerge receptoren........................................................................ 74
D. 𝜶-agonisten........................................................................................ 77
1. fenylethylaminen ................................................................................................. 77
2. imidazolinen & aanverwante verbindingen .................................................................... 80
1
, 2.1 aminoimidazolinen (guanidinederivaten)............................................................... 81
d) 𝜶-antagonisten ...................................................................................... 82
1. 𝛼1-antagonisten ................................................................................................... 82
2. 𝛼2-antagonisten ................................................................................................... 83
e) toepassingen van 𝜶-adrenerge liganden ....................................................... 83
f) ß-adrenerge receptoren ........................................................................... 84
g) ß-agonisten ........................................................................................... 86
A. Astma ............................................................................................................... 89
I. ß-antagonisten....................................................................................... 92
1. niet-selectieve ß-antagonisten .................................................................................. 93
2. selectieve ß1 antagonisten ....................................................................................... 95
3. partiële ß-agonisten .............................................................................................. 97
4. gemengde 𝛼/ß antagonisten..................................................................................... 98
J. indirect werkende sympathicomimetica ....................................................... 99
5. histamine & de histaminerge receptoren .................................................. 101
A. inleiding.......................................................................................... 101
1. werking thv maagmucosa ...................................................................................... 102
2. werkingsmechanisme thv mastcellen ........................................................................ 103
B. farmacologisch effect v histamine ......................................................... 104
C. biosynthese & metabolisme van histamine ............................................... 104
D. structuur & eigenschappen van histamine ............................................... 105
E. histamine receptoren ............................................................................ 106
1. H1 – receptor..................................................................................................... 106
2. H2 – receptor..................................................................................................... 107
3. H3 – receptor..................................................................................................... 109
F. histamine – agonisten ............................................................................ 111
G. histamine H1-receptor antagonisten ....................................................... 112
1. Ar1 = (hetero)arylgroep, Ar2 = aryl(methyl)groep........................................................... 112
2. X = sp2 gehybridiseerd C-atoom of sp3 C gebonden aan O-atoom ........................................ 112
3. C-C in ringsysteem .............................................................................................. 113
4. arylgroepen aan elkaar gebonden tot tricyclische structuur, vb fenothiazines (x = n)................ 114
5. afwijkingen van de algemene structuur ..................................................................... 115
6. H1-antihistaminica met piperazinering ....................................................................... 115
7. mastcelstabilisatoren ........................................................................................... 117
H. klinisch gebruik van H1 – antagonisten .................................................... 117
I. H2 – receptor antagonisten & inverse agonisten............................................ 118
1. de ontwikkeling van cimetidine ............................................................................... 119
2. moleculen met een flexibele connectie ..................................................................... 129
J. anti-ulcereuse geneesmiddelen ............................................................... 130
1. inhibitie v zuursecretie & pepsine-activiteit ................................................................ 130
2. verhoging vd mucosale verdediging tegen autodigestie ................................................... 130
3. stimulatie vh herstel vd mucosa .............................................................................. 130
K. H3-antagonisten ................................................................................ 131
L. H4-antagonisten ................................................................................... 131
2
,4. dopamine & de dopaminerge receptoren .............................................. 132
A. biosynthese, metabolisme & stabiliteit van dopamine ................................. 132
B. verbindingen die interfereren met de dopaminerge neurotransmissie ............ 133
1. DOPA-decarboxylase inhibitoren .............................................................................. 133
2. MAO-inhibitoren ................................................................................................. 133
3. COMT-inhibitoren ............................................................................................... 134
4. dopamine release ............................................................................................... 134
5. “reuptake”-inhibitoren ......................................................................................... 134
6. synthese & vrijzetting dopamine ............................................................................. 134
C. classificatie vd dopaminerge receptoren ................................................. 135
D. preferentiële conformatie van dopamine thv de receptor............................ 138
E. dopamine-agonisten .............................................................................. 139
1. fenylethylaminen ............................................................................................... 139
2. 3-fenylpiperiden ................................................................................................ 139
3. aporfinen & 2-aminotetralinen ................................................................................ 140
4. ergotderivaten................................................................................................... 142
5. andere verbindingen ............................................................................................ 143
F. ziekte van Parkinson ............................................................................. 144
G. dopamine-antagonisten ....................................................................... 147
1. klassieke antipsychotica ....................................................................................... 147
1.1 fenothiazinen............................................................................................. 148
1.2 thioxantheen derivaten ................................................................................. 150
1.3 butyrofenonen ........................................................................................... 151
1.4 diarylbutylamines ........................................................................................ 152
1.5 benzamiden .............................................................................................. 153
2. atypische neuroleptica (antipsychotica) ..................................................................... 154
3. perifere dopamine-antagonisten .............................................................................. 157
5. serotonine & de serotonerge receptoren .............................................. 162
A. biosynthese van serotonine.................................................................. 162
B. verbindingen die interfereren met de serotonerge neurotransmissie ............. 163
1. monoamino-reuptake inhibitoren ............................................................................. 163
C. geneesmiddelen met antidepressive werking............................................ 167
o monoamine-reuptake inhibitoren ............................................................................. 167
o mao-inhibitoren (MAO-I)....................................................................................... 167
o 2-Adrenerge antagonisten .................................................................................... 168
4. antidepressieve benzodiazepinen............................................................................. 168
5. Lithiumzouten (lithiumcarbonaat) ............................................................................ 168
6. esketamine ....................................................................................................... 168
D. serotonerge (5-HT-) receptoren ............................................................ 169
E. biologisch & farmacologisch effect van serotonine-receptor-binende liganden..... 171
o 5-HT1A ............................................................................................................. 172
2. 5-HT1D ............................................................................................................. 174
3. 5-HT2A ............................................................................................................. 175
4. 5-HT2C ............................................................................................................. 176
5. 5-HT3 .............................................................................................................. 177
6. 5-HT4 .............................................................................................................. 177
F. gebruik van serotonine-agonisten & -antagonisten ........................................ 178
3
, G. nota betreffende migraine ................................................................... 179
6. aminozuurneurotransmitters ............................................................ 180
A. het GABA-neurotransmissie-systeem ...................................................... 180
1. structuur & biosynthese van GABA ........................................................................... 181
2. het GABA-neurotransmissiesysteem & de GABA-receptoren .............................................. 187
3 GABA-agonisten & GABA-antagonisten ....................................................................... 192
3.1 GABAA agonisten ......................................................................................... 193
3.2 GABAB agonisten & antagonisten ...................................................................... 193
4. 1,4-benzodiazepinen & de benzodiazepinereceptor (BZD) ................................................ 195
4.1 1,3-dihydro-2H-1,4-benzodiazepin-2-ones ........................................................... 202
4.2 2,3-dihydro-1H-1,4-benzodiazepines .................................................................. 203
4.3 2-amino-3H-1,4-benzodiazepines ...................................................................... 203
4.4 heteroaryl [e] [1,4] diazepines ......................................................................... 204
4.5 benzodiazepin-2-ones met d-modificaties ........................................................... 204
4.6 1,4-benzodiazepines met A-modificaties.............................................................. 205
4.7 diheteroaryl [A,F] [1,4] diazepines .................................................................... 205
4.8 verbindingen die rechtstreeks inwerken op de benzodiazepinereceptor ........................ 206
B. epilepsieën ...................................................................................... 208
1. werkingsmechanisme anti-epileptica ........................................................................ 210
7. enkefalines, endorfines & opiaatanalgetica .......................................... 214
A. indeling & behandeling van pijn ............................................................ 214
B. morfine & de opioïde receptoren .......................................................... 215
C. endogene opiumachtige peptiden (“natural painkillers”) ............................ 221
D. morfine-analogen (SAR van morfine-agonisten) ......................................... 225
1. morfinederivaten ............................................................................................... 225
2. morfinaanderivaten ............................................................................................. 227
3. 6,7-benzomorfaanderivaten ................................................................................... 228
4. fenylpiperidine & methadonederivaten ...................................................................... 229
5. oripavinederivaten .............................................................................................. 232
E. opiumachtige antagonisten & partiële agonisten .......................................... 233
1. perifeer werkende opiaatantagonisten ...................................................................... 233
F. het verband tussen morfine & enkefalines .................................................. 238
G. klinisch gebruik van opiaten................................................................. 241
1. agonisten voor perifere opiaatreceptoren in ileum ........................................................ 242
8. het arachidonzuurmetabolisme & inflammatie ...................................... 244
A. inleiding.......................................................................................... 244
B. metabolisme van arachidonzuur ............................................................ 246
1. de cyclo-oxygenase weg ....................................................................................... 246
1.1 inactivatie ................................................................................................ 249
1.1.1 Snelle (niet enzymatische) hydrolyse van prostacycline PGI2 tot 6-keto-PGF1αBovenste 5-
ring: O in ring .................................................................................................... 249
1.2 nota betreffende de nomenclatuur vd prostaglandines ........................................... 250
B. de lipo-oxygenase weg ......................................................................................... 251
C. receptoren ...................................................................................... 253
D. biologische activiteit .......................................................................... 254
1. prostaglandines.................................................................................................. 254
2. prostacyclinen ................................................................................................... 254
4
1. INHOUDSOPGAVE
2. Acetylcholine & de cholinerge receptoren ............................................... 7
A. inleiding............................................................................................. 7
1. Autonoom ZS ........................................................................................................ 8
1.1. Sympatisch ZS ................................................................................................ 8
1.2. Parasympatisch ZS ........................................................................................... 9
B. het neurotransmissieproces ................................................................... 12
C. de nicotinereceptor ............................................................................. 15
D. De muscarinereceptor .......................................................................... 19
1. M1-receptor ........................................................................................................ 21
2. M2-receptor ........................................................................................................ 23
3. M3-receptor ........................................................................................................ 23
E. structuur van acetylcholine ...................................................................... 24
F. SAR ..................................................................................................... 26
1. De nicotinereceptor .............................................................................................. 26
3.1. agonisten .................................................................................................... 26
3.2. antagonisten ................................................................................................ 30
3.2.1 ganglionblokkers ..................................................................................... 30
3.2.2 neuromusculaire blokkers (curares) ............................................................... 31
3.2.3 lokale anesthetica ................................................................................... 35
2. de muscarinereceptor ............................................................................................ 40
2.1 agonisten .................................................................................................... 40
2.2 antagonisten ................................................................................................ 45
2.2.1 solanaceae alkaloïden & synthetische analogen ................................................. 46
2.2.2 analogen met gewijzigde tropaanring............................................................. 48
2.2.3 analogen zonder esterfunctie ...................................................................... 49
2.2.4 andere muscarine antagonisten .................................................................... 50
G. biologische activiteit & therapeutisch gebruik van cholinerge agonisten ........... 51
1 Nicotine-agonisten ................................................................................................ 51
2 Nicotine-antagonisten ............................................................................................ 52
2.1 ganglionblokkers ............................................................................................ 52
2.2 neuromusculaire blokkers ................................................................................. 52
3 Muscarine-agonisten .............................................................................................. 53
4 Muscarine-antagonisten .......................................................................................... 54
H. acetylcholinesteraseremmers ................................................................. 56
1 reversibele, competitieve enzyminhibitoren .................................................................. 57
2 inhibitoren die een covalente binding vormen met de katalytische plaats van het
acetylcholinesterase (irreversibele inhibitoren) .................................................................... 58
3. (NOR)adrenaline & de adrenerge receptoren ........................................... 64
A. de adrenerge neurotransmissie ............................................................... 64
B. structuur van adrenaline: stereochemie & conformatie ................................ 73
C. 𝜶-adrenerge receptoren........................................................................ 74
D. 𝜶-agonisten........................................................................................ 77
1. fenylethylaminen ................................................................................................. 77
2. imidazolinen & aanverwante verbindingen .................................................................... 80
1
, 2.1 aminoimidazolinen (guanidinederivaten)............................................................... 81
d) 𝜶-antagonisten ...................................................................................... 82
1. 𝛼1-antagonisten ................................................................................................... 82
2. 𝛼2-antagonisten ................................................................................................... 83
e) toepassingen van 𝜶-adrenerge liganden ....................................................... 83
f) ß-adrenerge receptoren ........................................................................... 84
g) ß-agonisten ........................................................................................... 86
A. Astma ............................................................................................................... 89
I. ß-antagonisten....................................................................................... 92
1. niet-selectieve ß-antagonisten .................................................................................. 93
2. selectieve ß1 antagonisten ....................................................................................... 95
3. partiële ß-agonisten .............................................................................................. 97
4. gemengde 𝛼/ß antagonisten..................................................................................... 98
J. indirect werkende sympathicomimetica ....................................................... 99
5. histamine & de histaminerge receptoren .................................................. 101
A. inleiding.......................................................................................... 101
1. werking thv maagmucosa ...................................................................................... 102
2. werkingsmechanisme thv mastcellen ........................................................................ 103
B. farmacologisch effect v histamine ......................................................... 104
C. biosynthese & metabolisme van histamine ............................................... 104
D. structuur & eigenschappen van histamine ............................................... 105
E. histamine receptoren ............................................................................ 106
1. H1 – receptor..................................................................................................... 106
2. H2 – receptor..................................................................................................... 107
3. H3 – receptor..................................................................................................... 109
F. histamine – agonisten ............................................................................ 111
G. histamine H1-receptor antagonisten ....................................................... 112
1. Ar1 = (hetero)arylgroep, Ar2 = aryl(methyl)groep........................................................... 112
2. X = sp2 gehybridiseerd C-atoom of sp3 C gebonden aan O-atoom ........................................ 112
3. C-C in ringsysteem .............................................................................................. 113
4. arylgroepen aan elkaar gebonden tot tricyclische structuur, vb fenothiazines (x = n)................ 114
5. afwijkingen van de algemene structuur ..................................................................... 115
6. H1-antihistaminica met piperazinering ....................................................................... 115
7. mastcelstabilisatoren ........................................................................................... 117
H. klinisch gebruik van H1 – antagonisten .................................................... 117
I. H2 – receptor antagonisten & inverse agonisten............................................ 118
1. de ontwikkeling van cimetidine ............................................................................... 119
2. moleculen met een flexibele connectie ..................................................................... 129
J. anti-ulcereuse geneesmiddelen ............................................................... 130
1. inhibitie v zuursecretie & pepsine-activiteit ................................................................ 130
2. verhoging vd mucosale verdediging tegen autodigestie ................................................... 130
3. stimulatie vh herstel vd mucosa .............................................................................. 130
K. H3-antagonisten ................................................................................ 131
L. H4-antagonisten ................................................................................... 131
2
,4. dopamine & de dopaminerge receptoren .............................................. 132
A. biosynthese, metabolisme & stabiliteit van dopamine ................................. 132
B. verbindingen die interfereren met de dopaminerge neurotransmissie ............ 133
1. DOPA-decarboxylase inhibitoren .............................................................................. 133
2. MAO-inhibitoren ................................................................................................. 133
3. COMT-inhibitoren ............................................................................................... 134
4. dopamine release ............................................................................................... 134
5. “reuptake”-inhibitoren ......................................................................................... 134
6. synthese & vrijzetting dopamine ............................................................................. 134
C. classificatie vd dopaminerge receptoren ................................................. 135
D. preferentiële conformatie van dopamine thv de receptor............................ 138
E. dopamine-agonisten .............................................................................. 139
1. fenylethylaminen ............................................................................................... 139
2. 3-fenylpiperiden ................................................................................................ 139
3. aporfinen & 2-aminotetralinen ................................................................................ 140
4. ergotderivaten................................................................................................... 142
5. andere verbindingen ............................................................................................ 143
F. ziekte van Parkinson ............................................................................. 144
G. dopamine-antagonisten ....................................................................... 147
1. klassieke antipsychotica ....................................................................................... 147
1.1 fenothiazinen............................................................................................. 148
1.2 thioxantheen derivaten ................................................................................. 150
1.3 butyrofenonen ........................................................................................... 151
1.4 diarylbutylamines ........................................................................................ 152
1.5 benzamiden .............................................................................................. 153
2. atypische neuroleptica (antipsychotica) ..................................................................... 154
3. perifere dopamine-antagonisten .............................................................................. 157
5. serotonine & de serotonerge receptoren .............................................. 162
A. biosynthese van serotonine.................................................................. 162
B. verbindingen die interfereren met de serotonerge neurotransmissie ............. 163
1. monoamino-reuptake inhibitoren ............................................................................. 163
C. geneesmiddelen met antidepressive werking............................................ 167
o monoamine-reuptake inhibitoren ............................................................................. 167
o mao-inhibitoren (MAO-I)....................................................................................... 167
o 2-Adrenerge antagonisten .................................................................................... 168
4. antidepressieve benzodiazepinen............................................................................. 168
5. Lithiumzouten (lithiumcarbonaat) ............................................................................ 168
6. esketamine ....................................................................................................... 168
D. serotonerge (5-HT-) receptoren ............................................................ 169
E. biologisch & farmacologisch effect van serotonine-receptor-binende liganden..... 171
o 5-HT1A ............................................................................................................. 172
2. 5-HT1D ............................................................................................................. 174
3. 5-HT2A ............................................................................................................. 175
4. 5-HT2C ............................................................................................................. 176
5. 5-HT3 .............................................................................................................. 177
6. 5-HT4 .............................................................................................................. 177
F. gebruik van serotonine-agonisten & -antagonisten ........................................ 178
3
, G. nota betreffende migraine ................................................................... 179
6. aminozuurneurotransmitters ............................................................ 180
A. het GABA-neurotransmissie-systeem ...................................................... 180
1. structuur & biosynthese van GABA ........................................................................... 181
2. het GABA-neurotransmissiesysteem & de GABA-receptoren .............................................. 187
3 GABA-agonisten & GABA-antagonisten ....................................................................... 192
3.1 GABAA agonisten ......................................................................................... 193
3.2 GABAB agonisten & antagonisten ...................................................................... 193
4. 1,4-benzodiazepinen & de benzodiazepinereceptor (BZD) ................................................ 195
4.1 1,3-dihydro-2H-1,4-benzodiazepin-2-ones ........................................................... 202
4.2 2,3-dihydro-1H-1,4-benzodiazepines .................................................................. 203
4.3 2-amino-3H-1,4-benzodiazepines ...................................................................... 203
4.4 heteroaryl [e] [1,4] diazepines ......................................................................... 204
4.5 benzodiazepin-2-ones met d-modificaties ........................................................... 204
4.6 1,4-benzodiazepines met A-modificaties.............................................................. 205
4.7 diheteroaryl [A,F] [1,4] diazepines .................................................................... 205
4.8 verbindingen die rechtstreeks inwerken op de benzodiazepinereceptor ........................ 206
B. epilepsieën ...................................................................................... 208
1. werkingsmechanisme anti-epileptica ........................................................................ 210
7. enkefalines, endorfines & opiaatanalgetica .......................................... 214
A. indeling & behandeling van pijn ............................................................ 214
B. morfine & de opioïde receptoren .......................................................... 215
C. endogene opiumachtige peptiden (“natural painkillers”) ............................ 221
D. morfine-analogen (SAR van morfine-agonisten) ......................................... 225
1. morfinederivaten ............................................................................................... 225
2. morfinaanderivaten ............................................................................................. 227
3. 6,7-benzomorfaanderivaten ................................................................................... 228
4. fenylpiperidine & methadonederivaten ...................................................................... 229
5. oripavinederivaten .............................................................................................. 232
E. opiumachtige antagonisten & partiële agonisten .......................................... 233
1. perifeer werkende opiaatantagonisten ...................................................................... 233
F. het verband tussen morfine & enkefalines .................................................. 238
G. klinisch gebruik van opiaten................................................................. 241
1. agonisten voor perifere opiaatreceptoren in ileum ........................................................ 242
8. het arachidonzuurmetabolisme & inflammatie ...................................... 244
A. inleiding.......................................................................................... 244
B. metabolisme van arachidonzuur ............................................................ 246
1. de cyclo-oxygenase weg ....................................................................................... 246
1.1 inactivatie ................................................................................................ 249
1.1.1 Snelle (niet enzymatische) hydrolyse van prostacycline PGI2 tot 6-keto-PGF1αBovenste 5-
ring: O in ring .................................................................................................... 249
1.2 nota betreffende de nomenclatuur vd prostaglandines ........................................... 250
B. de lipo-oxygenase weg ......................................................................................... 251
C. receptoren ...................................................................................... 253
D. biologische activiteit .......................................................................... 254
1. prostaglandines.................................................................................................. 254
2. prostacyclinen ................................................................................................... 254
4
