Abstract Background: γ-Aminobutyric acid type A (GABAA) receptors are the main inhibitory receptors in the CNS. Benzodiazepines (BZDs) are positive allosteric modulators at the BZD site but cause sedation. Pitrazepin is unusual among piperazine-containing psychotropics: it binds the BZD site yet acts as an antagonist or negative modulator, suggesting a path to anxiolytic or antipsychotic effects with less sedation. Objective: To analyze structure–activity relationships (SAR) for piperazine-containing tricyclic scaffolds related to pitrazepin and to model their binding at the BZD site of GABAA receptors, guiding future experimental research. Methods: Literature IC50 values (μM) were gathered for representative piperazine/tricyclic analogs. Ligand docking was performed on a homologous pentameric ligand-gated ion channel (ELIC) used as a model for the GABAA BZD site, followed by qualitative analysis of key residues reported to correspond to human GABAA positions (e.g., Y159). No synthetic procedures are included. Results: Across the series, active ligands feature a 6-7-6 tricyclic pharmacophore with a central oxazine or thiapine ring and a piperazine group; potency allows limited substitution at the 7-position. Docking predicts a conserved hydrogen-bond interaction near Arg194 and stabilizing contacts involving Gln146, Asp144, and His169. Re-orienting toward Gln125 and Val147 correlates with decreased aromatic stacking and lower predicted affinity. Literature data and docking together rank pitrazepin among the stronger binders in the series. Conclusion: A clear SAR pattern emerges for piperazine-containing GABAA ligands at the BZD site. Predicted interactions explain reported activities and emphasize residues, such as those analogous to Y159, as critical for binding. These findings encourage targeted biological testing of pitrazepin and similar compounds as negative allosteric modulators aimed at maintaining efficacy while reducing BZD-like sedation.
