ABSTRACT
The goal of retrometabolic drug design is: "to design safe, locally active compounds with an improved therapeutic index". Here we describe two cases from our own practice, talampanel and omeprazole.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/metabolism , Benzodiazepines/chemical synthesis , Benzodiazepines/metabolism , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Omeprazole/chemical synthesis , Omeprazole/metabolism , Anticonvulsants/pharmacology , Benzodiazepines/pharmacology , Enzyme Inhibitors/pharmacology , Indicators and Reagents , Omeprazole/pharmacology , Proton Pump Inhibitors , Structure-Activity RelationshipABSTRACT
The anxiolytic action of two 2,3-benzodiazepines: girisopam: GYKI 51,189 (EGIS 5810): (1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine), and GYKI 52,322 (EGIS 6775): (1-(4-aminophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine) was investigated in comparison to chlordiazepoxide and buspirone using three different animal models of anxiety: the lick conflict, the elevated plus maze and the open field methods in rats. Both 2,3-benzodiazepines exerted anxiolytic effect in all three tests used, however their pharmacological profile differs considerably from that of either chlordiazepoxide or buspirone. Using the animal models mentioned above the order of potency was GYKI 52,322 (EGIS 6775) > chlordiazepoxide > girisopam > buspirone.
Subject(s)
Anti-Anxiety Agents/pharmacology , Benzodiazepines/pharmacology , Buspirone/pharmacology , Chlordiazepoxide/pharmacology , Animals , Conflict, Psychological , Dose-Response Relationship, Drug , Electroshock , Exploratory Behavior/drug effects , Male , Rats , Rats, Inbred StrainsABSTRACT
The neuropharmacological effects of 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 52 322) were investigated and compared with those of chlordiazepoxide and chlorpromazine. This novel 2,3-benzodiazepine displays neuroleptic activity in the apomorphine-climbing (ED50 = 1.15 mg/kg i.p.) and swim-induced grooming (ED50 = 6.9 mg/kg i.p.) tests in mice and it inhibits the conditioned avoidance response in rats (ED50 = 8.2 mg/kg i.p. and 9.8 mg/kg p.o.). However, it does not antagonize apomorphine-evoked vomiting in dogs; or stereotypy, hypermotility and turning in rats even at as high a dose as 50 mg/kg i.p. On the other hand it is active in the hole board test in mice (MED (minimal effective dose) = 0.5 mg/kg i.p.) and in the lick conflict assay in rats (MED = 5 mg/kg i.p.), indicating anxiolytic property. It shows antiaggressive effect in the fighting mice test (ED50 = 8.1 mg/kg p.o.) and the carbachol-rage procedure in cats (active at 10 mg/kg i.p.) According to the biochemical findings, this compound does not bind to the central dopamine receptors (IC50 greater than 10(-4) mol/l), but it shows affinity to the 5-HT1 receptors (IC50 = 7.1 x 10(-6) mol/l) and inhibits brain cAMP-phosphodiesterase (IC50 = 2.4 x 10(-5) mol/l). The substance causes no elevation of dopamine turnover and serum prolactin level suggesting fewer side effects. So the term "atypical neuroleptic agent" is proposed to characterize this molecule.
