{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:27:51Z","timestamp":1760142471740,"version":"build-2065373602"},"reference-count":75,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Engrail Therapeutics, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 \u03b11\/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 \u03b12\/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 \u03b2-band power and decreased \u03b4- and \u03b8-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.<\/jats:p>","DOI":"10.3390\/cells14201575","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T09:45:01Z","timestamp":1760089501000},"page":"1575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomarker-Based Pharmacological Characterization of ENX-102, a Novel \u03b12\/3\/5 Subtype-Selective GABAA Receptor Positive Allo-Steric Modulator: Translational Insights from Rodent and Human Studies"],"prefix":"10.3390","volume":"14","author":[{"given":"Pauline","family":"Nettesheim","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2333 ZG Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3455-0209","authenticated-orcid":false,"given":"Krishna C.","family":"Vadodaria","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly E.","family":"Vanover","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura G. J. M.","family":"Borghans","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2333 ZG Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estibaliz","family":"Arce","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Brubaker","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Parks","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Serrats","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikram","family":"Sudarsan","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eve","family":"Taylor","sequence":"additional","affiliation":[{"name":"Engrail Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica","family":"Klaassen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0013-8355","authenticated-orcid":false,"given":"Frederik E.","family":"Stuurman","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2333 ZG Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel E.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, 2333 CL Leiden, The Netherlands"},{"name":"Department of Psychiatry, Leiden University Medical Center, 2333 ZG Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0165-6147(99)01413-3","article-title":"The \u2018ABC\u2019 of GABA Receptors","volume":"21","author":"Bormann","year":"2000","journal-title":"Trends Pharmacol. 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