2‑(4-Fluorophenyl)‑1H‑benzo[d]imidazole as a Promising Template for the Development of Metabolically Robust, α1β2γ2GABA‑A Receptor-Positive Allosteric Modulators

• Published in: ACS chemical neuroscience 2023-03, Vol.14 (6), p.1166-1180
• Main Authors: Marcinkowska, Monika, Fajkis-Zajączkowska, Nikola, Szafrańska, Katarzyna, Jończyk, Jakub, Siwek, Agata, Mordyl, Barbara, Karcz, Tadeusz, Latacz, Gniewomir, Kolaczkowski, Marcin
• Format: Article
• Language: English
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.2c00800

Modulation of α1β2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the α1/γ2 interface of the GABA-A receptor is limited to imidazo­[1,2-a]­pyridine derivatives that undergo rapid biotransformation. In response to a deficiency in the chemical repertoire of GABA-A receptors, we identified a series of 2-(4-fluorophenyl)-1H-benzo­[d]­imidazoles as positive allosteric modulators (PAMs) with improved metabolic stability and reduced potential for hepatotoxicity, where lead molecules 9 and 23 displayed interesting features in a preliminary investigation. We further disclose that the identified scaffold shows a preference for interaction with the α1/γ2 interface of the GABA-A receptor, delivering several PAMs of the GABA-A receptor. The present work provides useful chemical templates to further explore the therapeutic potential of GABA-A receptor ligands and enriches the chemical space of molecules suitable for the interaction with the α1/γ2 interface.