RESUMO
A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.
Assuntos
Analgésicos/síntese química , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Piridazinas/síntese química , Quinolinas/síntese química , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Alcinos/síntese química , Alcinos/química , Alcinos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Encéfalo/metabolismo , Doença Crônica , Constrição Patológica/complicações , Masculino , Dor/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Piridazinas/química , Piridazinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/patologia , Relação Estrutura-AtividadeRESUMO
Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.