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

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.

Imidazo[1,2-a]pyridine; Positive allosteric modulators of GABA-A receptor; Psychosis; Schizophrenia; Zolpidem.