title: 3-Aminomethyl Derivatives of 2-Phenylimidazo[1,2-a]-pyridine as Positive Allosteric Modulators of GABAAReceptor with Potential Antipsychotic Activity.
abstract: Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α1-GABAAreceptors would represent an original approach for the treatment of schizophrenia. This study presents the synthesis and biological evaluation of a series of fluorinated 3-aminomethyl derivatives of 2-phenylimidazo[1,2-a]-pyridine as potential antipsychotic agents. Compound 7 has a high affinity for GABAAreceptor (Ki= 27.2 nM), high in vitro metabolic stability, and antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 10 mg/kg). Compound 7 represents a promising point of entry in the course of development of antipsychotic agents with a nondopaminergic mechanism of action.
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Monika
authors.identifier: 0000-0002-4948-6617
authors.initials: M
authors.lastname: Marcinkowska
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Karcz
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Starowicz
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Słoczyńska
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Faculty of Pharmacy, Jagiellonian University Medical College , 9 Medyczna St., 30-688 Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.affiliation: Department of Psychiatry, Pomeranian Medical University , 1 Rybacka St., 70-204 Szczecin, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Samochowiec
authors.affiliation: Department of Pharmacology, Institute of Psychiatry and Neurology , 9 Sobieskiego St. 02-957 Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Mierzejewski
authors.affiliation: Department of Psychiatry, Medical University of Warsaw , ul. Nowowiejska 27, 00-665 Warsaw, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bienkowski
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D058785:GABA-A Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A
keywords: GABAergic transmission; Schizophrenia; amphetamine-induced hyperlocomotion; antipsychotic-like activity; fluorinated imidazo[1,2-a]pyridines; positive allosteric modulators of GABAA receptor; psychosis; zolpidem; γ-aminobutyric acid