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

Loredana Salerno, Valeria Pittalà, Maria N. Modica, Maria A. Siracusa, Sebastiano Intagliata, Alfredo Cagnotto, Mario Salmona, Rafał Kurczab, Andrzej J. Bojarski, Giuseppe Romeo

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)716-726
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume85
DOIs
Publication statusPublished - Oct 6 2014

Fingerprint

Receptor, Serotonin, 5-HT1A
Molecular modeling
Structure-Activity Relationship
Ligands
Serotonin Receptors
Dermatoglyphics
Carbon
Derivatives
Amino Acids
benzoxazolone
serotonin 7 receptor

Keywords

  • LCAP
  • Ligands
  • Receptors
  • Serotonin

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology
  • Medicine(all)

Cite this

Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands. / Salerno, Loredana; Pittalà, Valeria; Modica, Maria N.; Siracusa, Maria A.; Intagliata, Sebastiano; Cagnotto, Alfredo; Salmona, Mario; Kurczab, Rafał; Bojarski, Andrzej J.; Romeo, Giuseppe.

In: European Journal of Medicinal Chemistry, Vol. 85, 06.10.2014, p. 716-726.

Research output: Contribution to journalArticle

Salerno, Loredana ; Pittalà, Valeria ; Modica, Maria N. ; Siracusa, Maria A. ; Intagliata, Sebastiano ; Cagnotto, Alfredo ; Salmona, Mario ; Kurczab, Rafał ; Bojarski, Andrzej J. ; Romeo, Giuseppe. / Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT7 and 5-HT1A receptor ligands. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 85. pp. 716-726.
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