Targeting GABAergic Hypofunction Associated with Schizophrenia: Identification of α1β2γ2GABA-A Receptor Ligands with Neuroprotective and Antipsychotic Properties

Clinical evidence has demonstrated significant hypofunction of GABAergic neurotransmission in patients with schizophrenia, likely contributing to the onset of psychotic symptoms. These symptoms can be alleviated by α1β2γ2GABA-A receptor ligands, which have previously shown antipsychotic activity. Building on this foundation, we synthesized and characterized various derivatives of 2-phenylimidazo[1,2-<i>a</i>]-pyridine containing cyclic amine moieties at the amide backbone to identify potent ligands and expand the chemical space of α1β2γ2GABA-A receptor ligands. The synthesized compounds exhibited <i>K</i>_i values ranging from 25.0 to 7822.5 nM and positive allosteric properties at α1β2γ2GABA-A receptors. Selected compounds exhibited promising cellular permeability properties, high metabolic stability, and neuroprotective activity. A representative derivative of this series elicited antipsychotic-like properties, reversing amphetamine- and MK-801-induced hyperlocomotion without inducing sedative effects. Our findings indicate that α1β2γ2GABA-A ligands represent a promising strategy for the identification of potential antipsychotic agents with an original mechanism of action.