Structure–activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands

• Novel arylpiperazinylalkyl 2-benzoxazolone and 2-benzothiazolone derivatives.
• Potent dual ligands for 5-HT7 and 5-HT1A receptors amongst this new series were found.
• Docking studies were performed on 5-HT7 and 5-HT1A receptors binding sites.
• SIFt analysis identified amino acids selective for the interactions in both receptors.

A novel series of arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones 18–38 was designed, synthesized and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Compounds with a 2-benzothiazolone nucleus generally had affinity values higher than the corresponding 2-benzoxazolone compounds. In particular, derivatives possessing a six or seven carbon chain linker between 2-benzothiazolone and arylpiperazine had Ki values in the subnanomolar range for the 5-HT1A receptor and in the low nanomolar range for the 5-HT7 receptor, indicating that they may be interesting dual ligands. Molecular modeling studies revealed different docking poses for the investigated compounds in homology models of 5-HT1A and 5-HT7 receptors, which explained their experimentally determined affinities and general low selectivity. Additionally, structural interaction fingerprints analysis identified the important amino acid residues for the specific interactions of long-chain arylpiperazines within the binding pockets of both serotonin receptors.

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