Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands

Maria A. Siracusa, Loredana Salerno, Maria N. Modica, Valeria Pittalà, Giuseppe Romeo, Maria E. Amato, Mateusz Nowak, Andrzej J. Bojarski, Ilario Mereghetti, Alfredo Cagnotto, Tiziana Mennini

Research output: Contribution to journalArticle

Abstract

A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT1A and 5-HT2A serotonergic, α1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT1A receptor was used to explain the influence of spacer length on ligands affinity.

Original languageEnglish
Pages (from-to)4529-4538
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number15
DOIs
Publication statusPublished - Aug 14 2008

ASJC Scopus subject areas

  • Organic Chemistry

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    Siracusa, M. A., Salerno, L., Modica, M. N., Pittalà, V., Romeo, G., Amato, M. E., Nowak, M., Bojarski, A. J., Mereghetti, I., Cagnotto, A., & Mennini, T. (2008). Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands. Journal of Medicinal Chemistry, 51(15), 4529-4538. https://doi.org/10.1021/jm800176x