Biomarker-Based Pharmacological Characterization of ENX-102, a Novel α2/3/5 Subtype-Selective GABAA Receptor Positive Allo-Steric Modulator: Translational Insights from Rodent and Human Studies.

Gamma-aminobutyric acid type A receptors (GABAARs) are pentameric ligand-gated ion channels essential for inhibitory neurotransmission in the central nervous system. Subtype-specific expression patterns of GABAAR subunits underlie their diverse roles in regulating anxiety, motor function, and sedation. While non-selective GABAAR positive allosteric modulators (PAMs), such as benzodiazepines, are clinically effective anxiolytic drugs, their non-selective activity across α1/2/3/5 subunit-containing GABAARs leads to sedation, cognitive impairment, and risk of dependence. To address this, we evaluated ENX-102, a novel GABAAR PAM, which exhibits selectivity for α2/3/5 subunits. In rodents, ENX-102 demonstrated dose-dependent anxiolytic-like activity following acute and sub-chronic administration, without sedation. ENX-102 exhibited a dose-dependent quantitative electroencephalography (qEEG) spectral signature in rodents that was distinct from that of benzodiazepines. In a double-blind, placebo-controlled, multiple-ascending dose study in healthy human volunteers, ENX-102 was evaluated using the NeuroCart, a CNS test battery including saccadic peak velocity (SPV), adaptive tracking, pupillometry, body sway, the Bond and Lader Visual Analog Scale (VAS), the Visual Verbal Learning Task (VVLT), and qEEG. ENX-102 produced reductions in SPV that were indicative of central target engagement, with minimal effects on alertness and motor coordination, which is consistent with subtype-selective GABAAR targeting. Notably, qEEG revealed increased β-band power and decreased δ- and θ-band activity, which were distinct from the spectral profile of non-selective PAMs, supporting translational alignment with preclinical findings. Across dose levels, ENX-102 was well tolerated and exhibited favorable pharmacokinetics. These results support further clinical development of ENX-102 as a next-generation GABAAR subtype-selective anxiolytic drug.