Benzodiazepine derivatives for the treatment of neuropharmacological disorders and pain management: Docking investigations and in-vivo studies

Abstract

Benzodiazepines are well-known for their medicinal properties. The current study aimed to evaluate and seek new therapeutic possibilities of some of these compounds for addressing anxiety and pain. Four benzodiazepine derivatives were synthesized, characterized, and subjected to computational assessment of the GABAergic response upon interaction with human GABA-A receptors (PDBID: 6×3x) relative to the drug diazepam (DZP) to achieve the objective. Apart from the docking analysis, ADME analysis of the compounds was also performed. Following the in-silico evaluations, two of the synthesized compounds (designated as P3 and P4) were identified for subsequent in-vivo investigations utilizing laboratory rats to explore their anxiolytic potential in comparison to diazepam, and their analgesic efficacy relative to diclofenac sodium. The combination of in-silico and in-vivo assessments uncovered the binding sites of P4 (a fluoro derivative) and its potential as a superior anxiolytic drug compared to P3 (a hydroxy derivative) for analgesic relief. The ADME pharmacokinetic evaluation of the synthesized compounds by Lipinski rule of 5 suggested the oral bioavailability of these drugs. These findings are important as they provide valuable insights into the potential development of new anxiolytic and analgesic agents from the benzodiazepine derivatives that can be easily synthesized and developed into affordable drugs.