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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.

Author information

1
Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
2
Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: mmodica@unict.it.
3
IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milano, Italy.
4
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.

Abstract

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.

KEYWORDS:

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

PMID:
25128671
DOI:
10.1016/j.ejmech.2014.08.023
[Indexed for MEDLINE]

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