RESUMO
New arylpiperazine derivatives were prepared to identify highly selective and potent ligands for the 5-hydroxytryptamine 1A (5-HT(1A)) receptor as potential pharmacological tools in studies of central nervous system (CNS) disorders. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain, and arylpiperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in the nanomolar and subnanomolar ranges at 5-HT(1A) and moderate to no affinity for other relevant receptors (5-HT(2A), 5-HT(2C), D(1), D(2), alpha(1), and alpha(2)). The 4-[3-[4-(o-methoxyphenyl)piperazin-1-yl]propoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione, with K(i) = 0.021 nM, was the most active and selective derivative for the 5-HT(1A) receptor with respect to other serotonin receptors, whereas the most selective derivative for dopaminergic and adrenergic receptors was a CF(3)-substituted arylpiperazine. As a general trend, compounds with a piperazinylpropoxy chain showed a preferential affinity for the 5-HT(1A) receptor, suggesting that the alkyl chain length represents a critical structural feature in determining 5-HT(1A) receptor affinity and selectivity, as confirmed by the molecular modeling invoked for explaining the differential binding affinities of the new arylpiperazines.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Norbornanos/síntese química , Piperazinas/síntese química , Receptor 5-HT1A de Serotonina/metabolismo , Animais , Sítios de Ligação , Encéfalo/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Técnicas In Vitro , Masculino , Modelos Moleculares , Norbornanos/química , Norbornanos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Relação Estrutura-AtividadeRESUMO
An easy and convenient microwave-assisted synthesis of N-alkylated glycine methyl esters is described. Parallel and nonparallel combinatorial methods are described and compared. The described reactions are reductive alkylations of several aldehydes and glycine methyl ester in the presence of NaBH3CN. Good yields and short reaction times are the main aspects of these procedures.
Assuntos
Técnicas de Química Combinatória , Glicina/análogos & derivados , Micro-Ondas , Peptídeos/química , Peptídeos/síntese química , Aldeídos/química , Glicina/síntese química , Glicina/química , Estrutura MolecularRESUMO
One pot microwave-assisted synthesis of substituted 1,2,4-oxadiazoles in solvent and under solvent free condition was performed exploring the importance of some coupling reagents. Good yields and short reaction times were the main aspects of the methods.