RESUMO
This paper describes the synthesis of a series of new N-arylpiperazine derivatives of pyridine and 2-pyridone. The in vitro pharmacological study indicated that all of the compounds possess affinity towards α1-adrenoceptors, with exception of 6d, and are selective over α2 receptor. The most potent compound 5f displayed 62-fold α2/α1 selectivity with Ki value of 27.3 nM for α1 receptor. Selectivity of other ligands ranged from 6 to more than 146-fold. Hydrochlorides of selected compounds with the best α1-adrenoceptor affinity (7b, 7e, 7f, 8b) were tested in vivo (hypotensive activity test in rats) and the results proved their α-adrenoreceptor antagonistic activity. Furthermore, the lipophilicity of the investigated compounds has been assessed experimentally and in silico.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Piridinas/química , Piridonas/química , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/síntese química , Animais , Relação Dose-Resposta a Droga , Ligantes , Masculino , Estrutura Molecular , Piperazinas/síntese química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
A series of superlipophilic or highly lipophilic semisynthetic betulin derivatives was prepared and their relative lipophilicity was measured by reversed-phase thin-layer chromatography (RP-TLC) at different pH values using 1,4-dioxane-acetate buffer mixtures as mobile phases. Cholesterol, 17beta-estradiol and pure betulin were used as the reference compounds. Linear relationships were found between R(M) values and 1,4-dioxane concentrations in the mobile phases. LogP values were also calculated with computer programs ACD/LogP (ChemSketch 11.0, Advanced Chemistry Development Inc.) and ClogP (Daylight Chemical Information Systems Inc.). The empirical and theoretical data were compared, and the R(M0) values correlated well with logP. Two of the synthesized betulin derivatives are reported for the first time.
Assuntos
Antineoplásicos Fitogênicos/química , Betula/química , Cromatografia de Fase Reversa , Cromatografia em Camada Fina , Triterpenos/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/isolamento & purificação , Lipídeos/química , Casca de Planta/química , Triterpenos/síntese química , Triterpenos/isolamento & purificaçãoRESUMO
Lipophilicty of 29 thiobarbituric acid derivatives were assessed by reversed-phase thin-layer chromatography using methanol: water mixtures as a mobile phase. A linear relationship was found between RM values and methanol concentrations in the mobile phase. The retention parameter, RM0, was related to theoretical partition coefficients calculated by means of different theoretical procedures (AlogPs, IAlogP, miLogP, logPKowwin, xlogP).
