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

  • Eur J Med Chem. 2016 Nov 29:124:456-467. doi: 10.1016/j.ejmech.2016.08.059.
Monika Marcinkowska  1 ,  Marcin Kołaczkowski  2 ,  Krzysztof Kamiński  2 ,  Adam Bucki  2 ,  Maciej Pawłowski  2 ,  Agata Siwek  2 ,  Tadeusz Karcz  2 ,  Barbara Mordyl  2 ,  Gabriela Starowicz  2 ,  Paulina Kubowicz  2 ,  Elżbieta Pękala  2 ,  Anna Wesołowska  2 ,  Jerzy Samochowiec  3 ,  Paweł Mierzejewski  4 ,  Przemyslaw Bienkowski  4
Affiliations
  • 1. Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland. Electronic address: [email protected].
  • 2. Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
  • 3. Pomeranian Medical University, 1 Rybacka St., 70-204 Szczecin, Poland.
  • 4. Institute of Psychiatry and Neurology, 9 Sobieskiego St., 02-957 Warsaw, Poland.
PMID: 27598234 DOI: 10.1016/j.ejmech.2016.08.059
Abstract

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.

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