Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives
Anna Czopek,
Anna Partyka,
Adam Bucki,
Maciej Pawłowski,
Marcin Kołaczkowski,
Agata Siwek,
Monika Głuch-Lutwin,
Paulina Koczurkiewicz,
Elżbieta Pękala,
Anna Jaromin,
Bożena Tyliszczak,
Anna Wesołowska,
Agnieszka Zagórska
Affiliations
Anna Czopek
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
Anna Partyka
Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
Adam Bucki
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
Maciej Pawłowski
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
Marcin Kołaczkowski
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
Agata Siwek
Department of Pharmacobiology, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, Poland
Monika Głuch-Lutwin
Department of Pharmacobiology, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, Poland
Paulina Koczurkiewicz
Department of Pharmaceutical Biochemistry, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, Poland
Elżbieta Pękala
Department of Pharmaceutical Biochemistry, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, Poland
Anna Jaromin
Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, 50-383 Wroclaw, Poland
Bożena Tyliszczak
Faculty of Materials Engineering and Physics, Cracow University of Technology, Institute of Materials Science, 24 Warszawska Street, 31-155 Krakow, Poland
Anna Wesołowska
Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
Agnieszka Zagórska
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.
