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Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

ABSTRACT: 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.

SUBMITTER: Czopek A 

PROVIDER: S-EPMC7504677 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

Czopek Anna A   Partyka Anna A   Bucki Adam A   Pawłowski Maciej M   Kołaczkowski Marcin M   Siwek Agata A   Głuch-Lutwin Monika M   Koczurkiewicz Paulina P   Pękala Elżbieta E   Jaromin Anna A   Tyliszczak Bożena B   Wesołowska Anna A   Zagórska Agnieszka A  

Molecules (Basel, Switzerland) 20200825 17

In this study, a series of compounds derived from 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT<sub>1A</sub> and 5-HT<sub>7</sub> receptor affinities. Based on in vitro  ...[more]

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