Design, synthesis, and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives with potential antipsychotic activity

雑誌名: European Journal of Medicinal Chemistry
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著者: Monika Marcinkowska, Marcin Kołaczkowskia, Krzysztof Kamińskia, Adam Buckia, Maciej Pawłowskia, Agata Siweka, Tadeusz Karcza, Barbara Mordyla, Gabriela Starowicza, Paulina Kubowicza, Elżbieta Pękalaa, Anna Wesołowskaa, Jerzy Samochowiecb, Paweł Mierzejewskic, Przemyslaw Bienkowskic

Based on our recent finding that α1 selective GABA-A receptor potentiator—zolpidem—(a hypnotic drug) exerts antipsychotic-like effects in rats, we developed a series of fluorinated imidazo[1,2-a]pyridine derivatives as potential novel antipsychotic agents. The selected compounds displayed high affinity and positive allosteric modulator properties at the GABA-A receptor, enhanced metabolic stability and lack of hepatotoxicity. The most promising compound 2-(2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylethanamide (26) showed antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 1 mg/kg) and was characterized by a longer duration of antipsychotic-like activity as compared to zolpidem. These results are an encouraging example of a compound with non-dopaminergic mechanism of action displaying antipsychotic activity and are a point of entry for the future studies in this field.