RESUMO
Two 5-HT1A antagonists, t-FCWAY and c-FCWAY, were developed as imaging agents for positron emission tomography (PET). In order to evaluate these compounds, hepatocytes from both human and rat were utilized to produce metabolites and LC-MS-MS was used to identify metabolites. These in vitro metabolism studies indicate that hydrolysis of the amide linkage is the major metabolism pathway for humans, whereas aromatic ring-oxidation is the major metabolism pathway for rat. The rat hepatocyte results correlate well with in vivo rat metabolism studies. Based on the structures of the metabolites, we have developed an extraction procedure to determine the concentration of the parent compound in plasma.
Assuntos
Cromatografia Líquida/métodos , Fígado/metabolismo , Espectrometria de Massas/métodos , Piperazinas/metabolismo , Piridinas/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/metabolismo , Animais , Extratos Celulares/química , Células Cultivadas , Radioisótopos de Flúor , Humanos , Concentração de Íons de Hidrogênio , Modelos Químicos , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacologia , Ratos , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Estereoisomerismo , Tomografia Computadorizada de Emissão/métodosRESUMO
N-(Tertiary aminoalkyl)dithiocarbamic acids and esters were synthesized and evaluated for their ability to inhibit neuronal nitric oxide synthase. Preliminary results show these compounds are able to act at the binding site for L-arginine and the conformationally restricted esters may have a second site of activity involving the cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin.
