Anti-anxiety agents = anxilolytics = ataractics = „minor tranquilizers“ ●drugs for treatment of conditions characterized with fear and anxiety © Oldřich Farsa 2011 Benzodiazepins ●binding of GABA to GABAA receptor ⇒ increase of Clchannel permeablity ⇒ ↑ conc. Clinside the neuronu ⇒ decrease of excitability ●benzodiazepins enhance GABA effectivity by lowering its concentration needed for channel opening Benzodiazepine receptor is a part of chloride channel (ionophore) Benzodiazepins amplify GABA-ergic inhibition of impulse conducting in CNS GABAA -receptor-chloride channel with marked binding sites for various types of inhibiting drugs Benzodiazepins 1,4-benzodiazepins 5 N 1 CH3 2 3 N 4 O 7 6 Cl 5 N 1 2 3 N 4 NH 7 6 Cl CH3 O 5 N 1 CH3 2 3 N 4 O 7 6 Cl OH diazepam Diazepamum PhEur ●also prevention of convulsions in neonates and babies Apaurin® , Diazepam Slovakofarma® chlordiazepoxid ●since 1960 ●N-oxide ●amidine structure enables forming of salts with acids Elenium® oxazepam Oxazepam Léčiva® Benzodiazepins 1,4-benzodiazepins Cl N N H N + O O - O N CH3 N O Cl N H N O Br N clonazepam Clonazepamum PhEur tetrazepam Tetrazepamum PhEur bromazepam Bromazepamum PhEur Lexaurin® Benzodiazepins 1,4-benzodiazepins R N N N + O O - OCH3 N N Cl CH3 N N Cl CH3 O O O - K + R = H nitrazepam R = F flunitrazepam (Rohypnol® ) medazepam Ansilan® potassium clonazepate Benzodiazepins Fused 1,4-benzodiazepins: 4H-imidazo[1,5-a] and 4H-[1,2,4]-triazolo[4,3-a][1,4]benzodiazepins N N N Cl NCH3 R N N NCH3 F Cl R = H alprazolam Frontin ® , Neurol ® , Xanax ® R = Cl triazolam midazolam Dormicum ® Benzodiazepins 1,5-benzodiazepins N N CH3 O Cl O clobazam Clobazamum PhEur ●also anticonvulsant Frisium® Benzodiazepins 2,3-benzodiazepins 5 H 4 CH3 N 3 N 2 1 O CH3 O CH3 CH3 6 7 O CH3 8 O CH3 R,S-(±): tofisopam Grandaxin® R-(+): dextofisopam ●anxiolytic, therapeutic of irritable colon and Crohn disease S-(-): levotofisopam ●anxiolytic Isosteric analogues of benzodiazepins: 1,3-dihydro-2H-thieno[2,3-e][1,4]-diazepins Cl N N O SCH3 CH3 clotiazepam Benzodiazepine receptor antagonist N NF O NCH3 O CH3 O CH3 flumazenil Flumazenilum PhEur ●treatment of intoxications Effects of benzodiazepins ●anxiolytic ●anticonvulsive, antiepileptic ●muscle relaxant ●sedative – hypnotic – general anaesthetic Mode of action ●alosteric effectors of GABAA -receptor ● enhance inhibitory effect of GABA which is proceeded by Clentrance into a cell ● increase of intracellular concentration of Clleads to decrease of membrane irritability ●there is a close correlation between benzodiazepins activity and their afinity to their receptor ●endogenous ligands are not yet known Structure-activity relationships (SAR) ●diazacykloheptane ring fused to an aromatic system is necessary for the effect ●fused benzene can be replaced with thiophene ●benzene rinng in pos. 5 can be replaced with pyridine without activity loss ●methyl in pos. 1 increases the activity ●electron-accepting substituents in pos. 7 increase the activity in the order F