Abstract

Background. The search for anxiolytics with an improved safety profile is a key task of modern neuropsychopharmacology. Promising candidates are 2,3-benzodiazepine derivatives (MPTD-01, BS34-20) and β-carboline (Carbacetam), which in preclinical studies have demonstrated anxiolytic activity in the absence of side effects characteristic of classical 1,4-benzodiazepines. Aim: to determine and compare the polypharmacological profiles of structurally distinct anxiolytic candidates MPTD-01, BS34-20 and Carbacetam to elucidate the molecular mechanisms of their action using in silico methods. Materials and methods. The interaction of the compounds with a panel of key central nervous system targets, including GABAergic (GABAA, GABAB , TSPO), glutamatergic (AMPA), neuropeptide receptors, and ion channels (Nav1.2), was analyzed using molecular docking (AutoDock Vina, UCSF ChimeraX). ADMET profiling was also performed to assess the pharmacokinetic properties of the compounds. Results. Carbaracetam demonstrated a potent multitarget profile with high predicted affinity for GABAA (-10.513 kcal/ mol), the ion channel Nav1.2 (-9.420 kcal/mol), and the translocator protein TSPO (-9.053 kcal/mol), as well as significant interaction with GABAB and AMPA receptors. In contrast, 2,3-benzodiazepine derivatives (BS34-20 and MPTD-01) showed a more focused effect, consisting in a balanced modulation of GABAA (binding energy up to -8.379 kcal/mol for BS34-20) and AMPA receptors. A favorable safety profile and the ability to overcome the blood-brain barrier were predicted for all compounds. Conclusion. The obtained data indicate that the favorable therapeutic profile of the studied compounds is due not to selectivity to a single target, but to a balanced interaction with several signaling pathways. Understanding these polypharmacological profiles created the basis for further experimental validation and rational design of safer neurotherapeutic agents