RESUMEN
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.
Asunto(s)
Aminas/química , Benzofenonas/química , Benzofenonas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Animales , Benzofenonas/síntesis química , Línea Celular , Perros , Humanos , Estructura Molecular , Ratas , Receptor de Bradiquinina B1/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Analgésicos/química , Antiinflamatorios no Esteroideos/química , Antagonistas del Receptor de Bradiquinina B1 , Ciclohexanos/química , Hidrocarburos Fluorados/química , Piridinas/química , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Animales Modificados Genéticamente , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Ciclohexanos/síntesis química , Ciclohexanos/farmacología , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor de Bradiquinina B1/genética , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Animales , Animales Modificados Genéticamente , Unión Competitiva/efectos de los fármacos , Humanos , Marcaje Isotópico , Ligandos , Ensayo de Unión Radioligante , Ratas , Receptor de Bradiquinina B1/química , Relación Estructura-Actividad , Radioisótopos de AzufreRESUMEN
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.