In vivo Evaluation of Substituted 3-Amino-1,4-benzodiazepines as Anti-depressant, Anxiolytic and Anti-nociceptive Agents

Abstract

Oxazepam (CAS 604-75-1) 4a served as building block in the synthesis of substituted 3-amino-1,4-benzodiazepines, which were subsequently tested in various CNS animal models. The hydroxy group of oxazepam was either activated as a chloride (Method A) or as a phosphor-oxy derivative (Method B) giving the desired 3-amino-1,4-benzodiapines 6a-6r in high yields with primary and secondary amines in a typical nucleophilic substitution reaction. Eighteen 3-substituted 1,4-benzodiazepines were prepared and served as new chemical entities and for lead structure discovery. The mixed cholecystokinin (CCK) antagonist 6e showed anxiolytic and antidepressant effects from 10 microg/kg in mice in the elevated x-maze test and the forced swimming test. The CCK1 antagonist 6 g has shown antidepressant effects from the same dose, but lacked anxiolytic properties. Both compounds potentiated at a dose of 0.5 mg/kg morphine antinociception with a maximum possible effect (MPE) about 35%. By assessing initially the MPE of antinocipection for the 18 newly synthesised benzodiazepines in the tail-flick test, 4 other benzodiazepines were found active. In further in vive evaluation the cyclohexyl derivative 6 i displayed anxiolytic, antidepressant and antinociceptive properties as single agent at a dose of 5 mg/kg without toxicity. The benzodiazepines 6i and 6p, which initially showed a higher MPE in terms of morphine potentiation (43/44%) showed analgesic effects as single agents, without having anxiolytic or antidepressant properties. The amino-piperidinyl derivative 6p displayed a similar dose-response relationship to morphine, but was 3 times more potent.

Antidepressant/Anxiolytic and Anti-Nociceptive Effects of Novel 2-Substituted 1,4-Benzodiazepine-2-ones

“…3-Substituted 1,4-benzodiazepines [19] were formed via the 3-chlorinated intermediates, which acted as CCK antagonists and their in vivo evaluation was recently published [20]. …”

“…The elevated x-maze and the light/dark box were applied to test for anxiolytic activity. Anilino-benzodiazepine 5k showed a low CCK binding activity and this was not further investigated as CCK antagonists previously developed from the 3-substituted series had a better potency [20]. The tail suspension and the forced swim test served as assays for antidepressant activity.…”

“…In a recent patent application, a series of 3-amino-1,4-benzodiazepine were claimed as CCK-antagonists [9]. Further, 1,3-substituted 1,4-benzodiazepine templates were developed into farnesyl-protein transferase inhibitors, which represent potentially useful anticancer agents [10] (Figure 1).…”

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

“…PNB-001 contains the N-phenyl-ethyl substituent, which is required for high CCK 2 / gastrin selectivity 15 . The mixed dual acting N-benzylated pyrrolone 7 (Table 1) is showing the expected pharmacological profile of a mixed CCK COMMUNICATION Journal Name antagonist 16 and its role in brain cancer is currently being elucidated.…”

Synthesis of β‐Lactam‐containing Pyrido[3′,2′:4,5]thieno[3,2‐e][1,4]diazepines

“…As 1,4‐diazepine derivatives are widely known as compounds representing broad spectrum of biological and pharmacological activities , synthesis of new fused polycyclic diazepines or their modification is an interesting and actual trend of modern heterocyclic chemistry. It is clear that replacement of benzene ring in benzodiazepine molecules with heterocyclic unit and/or fusion of any heterocycle (for example, azetidine) to one of the 1,4‐diazepine bonds can change useful properties of annelated 1,4‐diazepines and will provide new valuable substances.…”