(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, L. Hársing, Michael Spedding, Gyula Simig

Research output: Contribution to journalArticle

65 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

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Ligands
Skeleton
Nitrogen
Atoms
Receptor, Serotonin, 5-HT1A
Halogens
Serotonin Receptors
Anti-Anxiety Agents
Structure-Activity Relationship
Drinking
Substitution reactions
Pharmacology
Derivatives
Light
oxindole
2-oxindole
phenylpiperazine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Volk, B., Barkóczy, J., Hegedus, E., Udvari, S., Gacsályi, I., Mezei, T., ... 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

(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists. / Volk, Balázs; Barkóczy, József; Hegedus, Endre; Udvari, Szaboles; Gacsályi, István; Mezei, Tibor; Pallagi, Katalin; Kompagne, Hajnalka; Lévay, György; Egyed, András; Hársing, L.; Spedding, Michael; Simig, Gyula.

In: Journal of Medicinal Chemistry, Vol. 51, No. 8, 24.04.2008, p. 2522-2532.

Research output: Contribution to journalArticle

Volk, B, Barkóczy, J, Hegedus, E, Udvari, S, Gacsályi, I, Mezei, T, Pallagi, K, Kompagne, H, Lévay, G, Egyed, A, Hársing, L, Spedding, M & Simig, G 2008, '(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists', Journal of Medicinal Chemistry, vol. 51, no. 8, pp. 2522-2532. https://doi.org/10.1021/jm070279v
Volk B, Barkóczy J, Hegedus E, Udvari S, Gacsályi I, Mezei T et al. (Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists. Journal of Medicinal Chemistry. 2008 Apr 24;51(8):2522-2532. https://doi.org/10.1021/jm070279v
Volk, Balázs ; Barkóczy, József ; Hegedus, Endre ; Udvari, Szaboles ; Gacsályi, István ; Mezei, Tibor ; Pallagi, Katalin ; Kompagne, Hajnalka ; Lévay, György ; Egyed, András ; Hársing, L. ; Spedding, Michael ; Simig, Gyula. / (Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 8. pp. 2522-2532.
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AU - Gacsályi, István

AU - Mezei, Tibor

AU - Pallagi, Katalin

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AU - Lévay, György

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