Abstract
A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ2) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors.
Highlights
Long-chain arylpiperazines (LCAPs) constitute one of the largest classes of serotonin (5-HT), and dopamine (D) receptor ligands, and exhibit diverse actions on the central nervous system (CNS) [1,2,3,4]
Structure–activity relationship studies Following our previous studies [5], which suggest a preferential position of sulfonamide group in the β-position of the azinyl moiety, 3-isoquinolyl moiety was selected to design the analogs of aripiprazole
In a series of new isoquinolinyl derivatives, we focused our attention on the type of halogen substitution in a phenylpiperazine fragment to determine the role of the halogen bond in ligand complexes and target receptors
Summary
Long-chain arylpiperazines (LCAPs) constitute one of the largest classes of serotonin (5-HT), and dopamine (D) receptor ligands, and exhibit diverse actions on the central nervous system (CNS) [1,2,3,4]. Among this vast group, we recently developed LCAP analogs of aripiprazole, with quinoline- or isoquinoline-sulfamoyl moieties, which displayed a 5-HT/D multi-receptor binding profile [5,6,7,8]. Due to the highly flexible nature of a linker, various attempts have been made to determine the bioactive conformation of LCAPs
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