L-Quebrachitol Enhances Sedative Effect of Diazepam Through GABAergic Pathway: Animal and Computational Studies

Insomnia and other sleep disorders are becoming increasingly prevalent worldwide, while current sedative medications such as benzodiazepines, though effective, are often limited by side effects and dependency risks. Therefore, identifying safe natural compounds with sedative potential is of growing scientific and clinical interest. L-quebrachitol (LQL), a naturally occurring cyclitol compound with antioxidant, antimicrobial, and antidiabetic properties, has not been previously evaluated for its sedative effects. The aim of this study is to evaluate the potential sedative effects of LQL through both in vivo and in silico methods.

In this experiment, 2-day-old broiler chicks (Gallus gallus domesticus) were given thiopental sodium (10 mg/kg, intraperitoneal [ip]) to induce sleep. LQL (1, 5, and 10 mg/kg, ip) and diazepam (2 mg/kg, ip) were administered alone or together to assess their synergistic or antagonistic effects on chicks. To assess its potential for interacting with the GABA_A receptor (α1 and β2 subunits), a molecular docking study was carried out.

According to the in vivo investigation, the results indicate that LQL decreased the latency period while extending the animal's sleep duration time in a dose-dependent manner. Moreover, the combination of LQL-10 (10 mg/kg) and diazepam 2 (2 mg/kg) showed (p < 0.05) enhanced sedative effects significantly by decreasing latency time and prolonging sleeping duration. In addition, LQL has a moderate binding affinity of -5.3 kcal/mol against the GABA_A receptor (α1 and β2 subunits), but forms strong hydrogen bond interactions and similar amino acid residues with standard drug diazepam, suggesting potential therapeutic effects. Further, LQL also demonstrated promising pharmacokinetic properties and low toxicity.

These findings collectively enhance the potential of LQL as an effective sedative therapeutic agent. However, further research, including in vitro studies to confirm the molecular interactions and membrane permeability, followed by well-designed clinical trials, is necessary to fully establish LQL as a safe and effective sedative agent.