[en] The discovery of a new, safe, atypical antipsychotic remains an important challenge. To achieve this goal, a series of N-methylpiperazinopyrido[2,3-b] [1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5]- benzodiazepines were synthesized. The dopaminergic (D1, D2), serotonergic (5-HT2), and cholinergic (M) affinities, frequently remarked in the action mechanisms of antipsychotic drugs, were determined using their respective in vitro receptor binding assays. All affinities were reduced for each compound. Optimal substituents were found to be in the 2- or 8-position for the retention of affinities, while substitution at the 5-position by acyl or alkyl groups dramatically diminished binding affinities. Pyridobenzodiazepine derivatives, such as clozapine, were found to be inactive or only weakly effective against apomorphine-mediated stereotypes in rats. In an original and complex behavioral model developed in dogs and successfully used to differentiate distinct classes of psychotropic drugs and to discriminate between typical and atypical neuroleptic drugs, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b] [1,4]benzodiazepine (9), 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine (12), and 5-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,5]benzodiazepine (16) showed most of the behavioral characteristics previously described for neuroleptics. Their neurochemical profiles, particularly their 5-HT2/D2 pKi ratios, were compatible with an atypical antipsychotic effect. These compounds were selected for further investigation. The proposed modulations could lead to new possibilities for the pharmacochemistry of diarylazepines.
Liégeois, Jean-François ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Bruhwyler, J.
Damas, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Nguyen, T. P.
Chleide, E. M.
Mercier, M. G.
Rogister, Françoise A.
Delarge, J. E.
Language :
English
Title :
New Pyridobenzodiazepine Derivatives as Potential Antipsychotics: Synthesis and Neurochemical Study
Publication date :
23 July 1993
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
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