Development of a Novel GABAB Receptor Modulator as an Alternative to Phenibut: Insights from Molecular Modeling and In Vivo Studies

Introduction: Phenibut, a GABAB receptor agonist, is used for anxiety and insomnia but is limited by side effects like drowsiness and withdrawal symptoms. This study aimed to identify a novel GABAB receptor modulator with improved efficacy and safety. Methods: A drug database of 15,000 compounds was screened using the Tanimoto similarity coefficient, identifying three candidates. Molecular docking and dynamics simulations assessed their binding affinity and stability with the GABAB receptor. The lead compound, 3-[(2-oxo-2- phenylethyl)amino]benzoic acid (C1), was tested in vivo using a stress-induced Wistar rat model (n=20, male, 200–250 g), with phenibut as a reference. Anxiety-like behaviour was evaluated via the elevated plus maze, and pharmacokinetic properties were analyzed. Results: C1 exhibited superior binding affinity (ΔGbind = -8.5 kcal/mol) and stability compared to phenibut (-8.0 kcal/mol). In vivo, C1 significantly increased open-arm time (110.80 ± 26.10 min) compared to phenibut (57.80 ± 9.40 min, p<0.05), indicating reduced anxiety-like behaviour. C1 also showed favourable oral bioavailability and blood-brain barrier permeability. Discussion: Consistently, C1 demonstrated superior performance compared to phenibut, suggesting its potential as a more effective alternative for GABAB receptor modulation. Conclusion: C1 is a promising alternative to phenibut, demonstrating enhanced anxiolytic effects and a favourable safety profile. Further studies are warranted to confirm its clinical potential.