当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579.

Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579.

Abstract：

:In an attempt to increase the affinity of our antipsychotic lead compound LASSBio-579 (1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine; (2)) for the 5-HT(2A) receptor, we synthesized five new N-phenylpiperazine derivatives using a linear synthetic route and the homologation strategy. The binding profile of these compounds was evaluated for a series of dopaminergic, serotonergic and alpha-adrenergic receptors relevant for schizophrenia, using classical competition assays. Increasing the length of the spacer between the functional groups of (2) proved to be appropriated since the affinity of these compounds increased 3-10-fold for the 5-HT(2A) receptor, with no relevant change in the affinity for the D₂-like and 5-HT(1A) receptors. A GTP-shift assay also indicated that the most promising derivative (1-(4-(1-(4-chlorophenyl)-1H-pyrazol-4-yl) butyl)-4-phenylpiperazine) (LASSBio-1635) (6) has the expected efficacy at the 5-HT(2A) receptors, acting as an antagonist. Intraperitoneal administration of (6) prevented apomorphine-induced climbing behavior and ketamine-induced hyperlocomotion in mice, in a dose dependent manner. Together, these results show that (6) could be considered as a new antipsychotic lead compound.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Pompeu TE,Alves FR,Figueiredo CD,Antonio CB,Herzfeldt V,Moura BC,Rates SM,Barreiro EJ,Fraga CA,Noël F

doi

10.1016/j.ejmech.2013.05.027

keywords:

["5-HT(2A)","Antipsychotics","Homologation","LASSBio-579","N-Phenylpiperazine","Schizophrenia"]

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

122-34

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(13)00336-X

journal_volume

66

pub_type

杂志文章

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