Planejamento, síntese, biotransformação e avaliação farmacológica de novos candidatos a protótipos de fármacos antipsicóticos

• Ano de defesa: 2010
• Autor(a) principal: SILVA, Mirella Andrade
• Orientador(a): MENEGATTI, Ricardo
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/38995/0013000001mj2
• Idioma: por
• Instituição de defesa: Universidade Federal de Goiás
• Programa de Pós-Graduação: Mestrado em Ciências Farmacêuticas
• Departamento: Ciências da Saúde - Farmácia
• País: BR
• Palavras-chave em Português: Esquizofrenia; antipsicóticos; N-fenilpiperazínicos
• Palavras-chave em Inglês: schizophrenia; phenilpiperazine; antipsycotics
• Área do conhecimento CNPq: CNPQ::CIENCIAS DA SAUDE::FARMACIA
• Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tde/2109

In the scope of a research program that aim the design, synthesis and pharmacological evaluation of new lead-compounds, we will describe in this work the design of new N-phenylpiperazines derivatives originally designed from clozapine (27) and LASSBio 579 (40) that shows antagonist profile in dopaminergic receptors. The compound 1-(4-nitrophenyl)-4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (45) was submitted to in vitro pharmacology assay in brain rat tissues to evaluate the inhibitory activity of D2 dopaminergic receptors and 5-HT2A and 5-HT1A serotonergic. Besides synthetic and pharmacological works its realized biotransformation studies using filamentous fungi and resulted lower number of metabolites than previous studies of (40) biotransformation. Was observed a p-hydroxylated metabolites in the aromatic ring A of 1-(4-methoxyphenyl)-4-((1-phenyl-1H-pyrazol-4- yl)methyl)piperazine (44) and 1-(4-nitrophenyl)-4-((1-phenyl-1H-pyrazol-4- yl)methyl)piperazine (45) were isolated and purified. We concluded that substitution of the D ring contributes to protect from enzymatic metabolism, confirmed by lower number of produced metabolites by biotransformation of the compound (40) . In work, we concluded that the structural design and the synthetic methodology used was validated through structural characterization, but the compounds not show inhibitory profile of dopaminergics (D2) and serotonergics receptors (5-HT2A e 5-HT1A) in front of the reference atypical antipsychotic.