A new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity.
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.
Horváth
K
K
Institute for Drug Research, Budapest, Hungary.
Andrási
F
F
Berzsenyi
P
P
Pátfalusi
M
M
Patthy
M
M
Szabó
G
G
Sebestyén
L
L
Bagdy
E
E
Körösi
J
J
Botka
P
P
D000262:Adenylyl Cyclases / Q000378:metabolism; D000374:Aggression / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000633:toxicity; D014150:Antipsychotic Agents; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology* / Q000633:toxicity; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002415:Cats; D003220:Conflict, Psychological; D004569:Electroencephalography; D005260:Female; D006120:Grooming / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008970:Molecular Weight; D011388:Prolactin / Q000097:blood; D051381:Rats; D019966:Substance-Related Disorders / Q000523:psychology
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; C061627:Nerisopam; D011388:Prolactin; D000262:Adenylyl Cyclases