The dysfunction of gamma-aminobutyric acid (GABA) receptors is consistently reported in several psychiatric disorders, normal aging, and neurodegenerative disorders. Benzodiazepines (BZ) have broad anxiolytic effects, but due to their non-selectivity at GABA-A receptors they are associated with sedative, ataxic and amnesic side-effects, as well as dependence. The imidazodiazepine, GL-II-73, a positive allosteric modulator of GABAA receptors, is an example of a novel treatment for combined decreased cognition, anxiety and depression. GL-II-73 exerts positive allosteric modulation at the α<sub>5</sub> containing GABAA receptors, preferably, with weaker modulation at α 1,2,and 3 receptors. This agent selectively targets only GABAA receptors, including the α5- receptor subunit, as mentioned, to overcome chronic stress-induced mood symptoms and cognitive deficits, as well as detriments in neuronal morphology. It is also anxiolytic; a condition comorbid with depression. Several novel imidazodiazepine (IBZD) amide and oxadiazole ligands were synthesized based on the structure GL-II-73 and tested for anxiolytic and antidepressant activity in adult mice. Pro-cognitive activity was observed in adult mice subjected to chronic mild stress and in old mice. The design and synthesis of these novel imidazodiazepine amide and oxadiazole ligands will be presented in this poster.

Design and synthesis of analogues of GL-II-73 as potential combined pro-cognitive, anxiolytic and antidepressant therapy

ACS Spring 2022

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