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-a ]-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 K 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.
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