New pyridobenzodiazepine derivatives as potential antipsychotics: synthesis and neurochemical study

Abstract

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.

Crystal structure of bis(8-chloro-5-(4-methylpiperazinium-1-yl)pyrido- [2,3-b][1,5]benzoxazepine) fumarate - fumaric acid solvate (1:1), (C17H18ClN4O)2(C4H2O4) · C4H4O4

“…The titled compound, a fumarate salt of 8-chloro-5-(4-methylpiperazin-1 -yl)pyrido [2,3-i>] [ 1,5]benzoxazepine [2,3] also called JL13 was prepared as part of our study of dopamine receptors and related binding sites implicated in schizophrenia [1,4]. Extensive investigations have revealed a very promising antipsychotic profile in several preclinical models [5], The oxazepine ring has a boat conformation where the four C atoms of the outer ring junction are almost coplanar: the maximum deviation from their mean plane is 0.022(1) A (cf.…”

3-Methyl-6-(4-methylpiperazin-1-yl)-11H-pyrido[2,3-b][1,4]benzodiazepine

“…The compound was synthesized according to Li6geois et al (1993) at the laboratory of Medicinal Chemistry of Liege. Crystals were obtained by slow evaporation of a methanol solution at room temperature.…”

Synthesis and Pharmacological Studies for New Benzotriazole and Dibenzodiazepine Derivatives as Antipsychotic Agents

“…7,8 Although the use of atypical antipsychotic drug clozapine in treatment of schizophrenia avoided the main disadvantage of typical ones e.g. extrapyrimidal side effects, still its use is limited due to the ability to induce agranulocytosis sedation, dizziness, headache, nausea, vomiting (neurotoxicity) and other side effects.…”