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.
Highlights
Isoindole-1,3-diones and their N-substituted analogs have been a very interesting and topical research area due to their wide structural diversity and broad-spectrum biological activities.The sulphonamide and amide derivatives of N-phenyl-phthalimidedisplayed potent inhibitory activity on neutrophil recruitment, which correlated with their inhibitory effect on tumor necrosis factor α (TNF-α) level [1]
We describe the synthesis of a library of novel 4-methoxy-2,3-dihydro-1H-isoindole1,3-dione derivatives with various aminoalkyl moieties, as potential inhibitors of phosphodiesterase 10A (PDE10A) and serotonin receptor ligands
Among the synthesized and tested compounds, 1H-benzimidazole derivatives were identified as potent PDE10A inhibitors
Summary
Isoindole-1,3-diones (phthalimides) and their N-substituted analogs have been a very interesting and topical research area due to their wide structural diversity and broad-spectrum biological activities.The sulphonamide and amide derivatives of N-phenyl-phthalimide (compounds 3a–e and 4a–e, Figure 1)displayed potent inhibitory activity on neutrophil recruitment, which correlated with their inhibitory effect on tumor necrosis factor α (TNF-α) level [1]. The sulphonamide and amide derivatives of N-phenyl-phthalimide (compounds 3a–e and 4a–e, Figure 1). Exhibits anti-HIV-1 and anti-HIV-2 activity in CEM cell cultures [2]. The N-pyridinyl and N-quinolinyl substituted derivatives of phthalimides (compounds 80 and 120 , Figure 1) demonstrated cytotoxicity against the growth of a number of cultured cell-lines [3]. Figure 1) are potent T-type calcium channel blockers [4], whereas 1,3-dioxoisoindoline-5-carboxylic acid derivatives (compounds 2c0 and 3c0 , Figure 1) are potent xanthine oxidase inhibitors [5]. (ZE)-2-[4-(1-hydrazono-ethyl)phenyl]isoindoline-1,3-dione (compound 120 , Figure 1) has shown remarkable anti-microbial activity [6]. Potent acetylcholinesterase inhibitors (AChEIs) were identified in a group of 2-fluorinated-benzylamino-alkyl-isoindoline-1,3-diones [9], 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones [10] (compounds 60 and 120 , Figure 1) and
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