Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT(7) ligands and role of the aromatic substituents in binding to the target receptor.
Bioorg Med Chem
; 21(9): 2568-76, 2013 May 01.
Article
en En
| MEDLINE
| ID: mdl-23541835
ABSTRACT
It has been reported that 5-HT(7) receptors are promising targets of depression and neuropathic pain. 5-HT(7) receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT(7) modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT(7) receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1-24 and 1-26 showed the best binding affinities to the 5-HT(7) receptor with K(i) values of 43.0 and 46.0 nM, respectively. Structure-activity relationship study in conjunction with molecular docking study proposed that the 5-HT(7) receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH(3) substituents within the arylpiperazine and the other for biphenyl methoxy group.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperazinas
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Antagonistas de la Serotonina
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Compuestos de Bifenilo
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Receptores de Serotonina
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Descubrimiento de Drogas
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2013
Tipo del documento:
Article