RESUMO
A series of N-substituted 1-(2,3-dihydro-1, 4-benzodioxin-2-yl)methylamine derivatives with D(2) antagonist/5-HT(1A) partial agonist activity has been prepared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosis has led to compound 24, which showed good affinities for human D(2), D(3), and 5-HT(1A) receptors but significantly less affinity for human alpha(1) adrenoceptors and rat H(1) and muscarinic receptors. In rodents, 24 showed functional D(2)-like antagonism and 5-HT(1A) partial agonism. After oral dosing, 24 showed good activity in rodent antipsychotic tests and very little potential to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this promising profile of activity, 24 has been selected for clinical investigation as a novel antipsychotic agent with a predicted low propensity to cause EPS.
Assuntos
Antipsicóticos/síntese química , Dioxanos/síntese química , Antagonistas de Dopamina/síntese química , Piperidinas/síntese química , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Animais , Antipsicóticos/química , Antipsicóticos/metabolismo , Antipsicóticos/toxicidade , Encéfalo/metabolismo , Catalepsia/induzido quimicamente , Dioxanos/química , Dioxanos/metabolismo , Dioxanos/toxicidade , Antagonistas de Dopamina/química , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/toxicidade , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores 5-HT1 de Serotonina , Proteínas Recombinantes/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/toxicidade , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade , SuínosRESUMO
Some of the 28 investigated new derivatives show distinct anticholinergic activity. The greatest activity, that of 2-cyclohexyl-2-phenyl-5-piperidinodioxane-1,3 was greater than of the atropine sulfate.