RESUMO
Selective bradykinin (BK) B 1 receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B 1 receptor antagonists with excellent receptor occupancy in the CNS of hBK B 1 transgenic rats.
Assuntos
Aminas/química , Benzofenonas/química , Benzofenonas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzofenonas/síntese química , Linhagem Celular , Cães , Humanos , Estrutura Molecular , Ratos , Receptor B1 da Bradicinina/metabolismo , Relação Estrutura-AtividadeRESUMO
Selective bradykinin (BK) B(1) receptor antagonists have been shown to be antinociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure-activity relationships of the biphenyl moiety of the lead compound 1 provided a potent new structural class of BK B(1) receptor antagonists.
Assuntos
Analgésicos/química , Anti-Inflamatórios não Esteroides/química , Antagonistas de Receptor B1 da Bradicinina , Cicloexanos/química , Hidrocarbonetos Fluorados/química , Piridinas/química , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Cicloexanos/síntese química , Cicloexanos/farmacologia , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptor B1 da Bradicinina/genética , Relação Estrutura-AtividadeRESUMO
We have developed an efficient and selective radioligand, the [35S]-radiolabeled dihydroquinoxalinone derivative, 4, for an ex vivo receptor occupancy assay in transgenic rats over-expressing the human bradykinin B1 receptor.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Animais , Animais Geneticamente Modificados , Ligação Competitiva/efeitos dos fármacos , Humanos , Marcação por Isótopo , Ligantes , Ensaio Radioligante , Ratos , Receptor B1 da Bradicinina/química , Relação Estrutura-Atividade , Radioisótopos de EnxofreRESUMO
Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.