Journal
ACS CHEMICAL NEUROSCIENCE
Volume 8, Issue 6, Pages 1291-1298Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.6b00432
Keywords
Schizophrenia; psychosis; positive allosteric modulators of GABA(A) receptor; gamma-aminobutyric acid; fluorinated imidazo[1,2-a]pyridines; GABAergic transmission; antipsychotic-like activity; amphetamine-induced hyperlocomotion; zolpidem
Funding
- National Science Center, Poland [5887/B/P01/2011/40]
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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 al-GABAA receptors 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 GABA(A) receptor (K-I = 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.
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