Design, synthesis, and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives with potential antipsychotic activity.
Based on our recent finding that α1selective 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.
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland. Electronic address: monika.marcinkowska@uj.edu.pl.
Monika
M
Marcinkowska
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Marcin
M
Kołaczkowski
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Krzysztof
K
Kamiński
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Adam
A
Bucki
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Maciej
M
Pawłowski
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Agata
A
Siwek
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Tadeusz
T
Karcz
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Barbara
B
Mordyl
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Gabriela
G
Starowicz
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Paulina
P
Kubowicz
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Elżbieta
E
Pękala
Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.
Anna
A
Wesołowska
Pomeranian Medical University, 1 Rybacka St., 70-204 Szczecin, Poland.
Jerzy
J
Samochowiec
Institute of Psychiatry and Neurology, 9 Sobieskiego St., 02-957 Warsaw, Poland.
Paweł
P
Mierzejewski
Institute of Psychiatry and Neurology, 9 Sobieskiego St., 02-957 Warsaw, Poland.
Przemyslaw
P
Bienkowski
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D055724:Electrophysiological Phenomena / Q000187:drug effects; D054879:Halogenation; D056945:Hep G2 Cells; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism
D014150:Antipsychotic Agents; D011725:Pyridines; D011963:Receptors, GABA-A
Imidazo[1,2-a]pyridine; Positive allosteric modulators of GABA-A receptor; Psychosis; Schizophrenia; Zolpidem