| Summary: | 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 studies, the most potent compound, <b>18</b> (2-[4-(1<i>H</i>-benzimidazol-2-yl)butyl]-4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound <b>18</b> 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 <b>18</b> in a behavioral model of schizophrenia were also investigated.
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