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Potential combined pro-cognitive, anxiolytic and antidepressant properties of novel GABAA receptor positive modulators with preferential efficacy at the α5-subunit

By Thomas Damien Prevot, Guanguan Li, Aleksandra Vidojevic, Keith A Misquitta, Corey Fee, Anja Santrac, Daniel E Knutson, Michael R Stephen, Revathi Kodali, Nicolas M Zahn, Leggy A. Arnold, Petra Scholze, Janet L Fisher, Bojan D. Marković, Mounira Banasr, Jim Cook, Miroslav Savic, Etienne Sibille

Posted 29 May 2018
bioRxiv DOI: 10.1101/332908

Altered γ-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging and neurodegenerative disorders, and reduced function of somatostatin-expressing GABA interneurons is associated with both mood and cognitive symptoms. Somatostatin-neurons signal in part through α-subunit containing GABAA receptors (α5-GABAA-Rs) which are localized in brain regions implicated in emotion and cognition. We hypothesize that enhancing α5-GABAA-R activity has therapeutic potential for both mood and cognitive symptoms in stress-based and aging rodent models. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands, tested them for positive allosteric modulation at α5-GABAA-R (α5-PAM), pharmacokinetic properties, and for anxiolytic and antidepressant activities in adult mice. Pro-cognitive activity was tested in adult mice submitted to chronic stress and in old mice. Diazepam (DZP), with broad PAM activity at GABAA-Rs, was used as a control. Three novel IBZD amide ligands (GL-II-73, GL-II-74 and GL-II-75) demonstrated adequate brain penetration, affinity and α5-PAM activity, and metabolic stability for in vivo studies. GL-II-73/74/75 showed significant anxiolytic and antidepressant efficacies in adult mice. GL-II-73 and GL-II-75 significantly reversed cognitive deficits induced by stress or occurring throughout normal aging. This activity was maintained after sub-chronic administration for GL-II-73. In contrast DZP displayed anxiolytic but no antidepressant or pro-cognitive activities. We demonstrate for the first time the potential for combined anxiolytic, antidepressant and pro-cognitive therapeutic, mediated by newly designed IBDZ amide ligands with efficacy at α5-GABAA-Rs. These results suggest a novel therapeutic approach targeting both mood and cognitive symptoms in depression and/or aging.

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