Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach.
J Med Chem
; 55(22): 9735-50, 2012 Nov 26.
Article
em En
| MEDLINE
| ID: mdl-23043306
ABSTRACT
A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Dopaminérgicos
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Dopamina
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Serotonina
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Agonistas do Receptor de Serotonina
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Antagonistas dos Receptores de Dopamina D2
Tipo de estudo:
Diagnostic_studies
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Screening_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article