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Eur J Med Chem. 2014 Oct 6;85:716-26. doi: 10.1016/j.ejmech.2014.08.023. Epub 2014 Aug 7.

Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT(7) and 5-HT(1A) receptor ligands.

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Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address:
IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy.
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.


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.


5-HT(1A); 5-HT(7); LCAP; Ligands; Receptors; Serotonin

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