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The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT 2A/6/7 and D 2 receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg), outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding comparator anxiolytics. In contrast to the existing psychotropic agents tested, the novel chemotypes did not negatively impact cognition. At a chronic dose regimen (25 days), 11 did not induce significant metabolic or adverse blood pressure disturbances. These promising therapeutic-like activities and benign safety profiles make the novel chemotypes potential treatment options for dementia patients.

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.

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