(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists

Balázs Volk, József Barkóczy, Endre Hegedus, Szaboles Udvari, István Gacsályi, Tibor Mezei, Katalin Pallagi, Hajnalka Kompagne, György Lévay, András Egyed, Lásló G. Hársing, Michael Spedding, Gyula Simig

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66 Citations (Scopus)

Abstract

A series of potent 5-hydroxytryptamine7 (5-HT7) ligands has been synthesized that contain a 1,3-dihydro2H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT7 and 5-HT 1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT7 receptor. According to the structure-activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindole skeleton and the basic nitrogen atom are the most potent ligands. Concerning the basic group, besides the moieties of the 4-phenylpiperazine type, halophenyl-1,2,3,6-tetrahydropyridines also proved to be 5-HT7 receptor-ligands. Because of halogen substitution on the aromatic rings, good metabolic stability could be achieved. A representative of the family, 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1, 3-dihydro-2H-indol-2-one (9e′) exhibited selective 5-HT7 antagonist activity (K: = 0.79 nM). The in vivo pharmacological potencies of these 5-HT7 receptor-ligands were estimated by the conflict drinking (Vogel) and the light-dark anxiolytic tests.

Original languageEnglish
Pages (from-to)2522-2532
Number of pages11
JournalJournal of Medicinal Chemistry
Volume51
Issue number8
DOIs
Publication statusPublished - Apr 24 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Volk, B., Barkóczy, J., Hegedus, E., Udvari, S., Gacsályi, I., Mezei, T., Pallagi, K., Kompagne, H., Lévay, G., Egyed, A., Hársing, L. G., Spedding, M., & Simig, G. (2008). (Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists. Journal of Medicinal Chemistry, 51(8), 2522-2532. https://doi.org/10.1021/jm070279v