RESUMEN
Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Piperazinas/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Ratones , Piperazinas/química , Piperazinas/farmacología , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
Further SAR studies on novel histamine H(3) receptor antagonists are presented. Compound 14bb is a potent antagonist of both the rat cortical and human clone receptors, and is demonstrated to act functionally as an antagonist in an in vivo mouse dipsogenia model.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Oxadiazoles/química , Oxadiazoles/farmacología , Receptores Histamínicos H3/química , Receptores Histamínicos H3/efectos de los fármacos , Animales , Humanos , Ligandos , Ratones , Modelos Animales , Estructura Molecular , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
Novel 4'-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H(3)receptors. Most compounds were highly potent and selective for human and rat H(3) receptors and selected examples such as A-349821 showed functional antagonism of H(3) receptors in vitro and in a mouse dipsogenia model.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Aminas/síntesis química , Aminas/farmacología , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cromatografía Líquida de Alta Presión , Clonación Molecular , Perros , Relación Dosis-Respuesta a Droga , Conducta de Ingestión de Líquido/efectos de los fármacos , Haplorrinos , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ensayo de Unión Radioligante , Ratas , Receptores de Amina Biogénica/efectos de los fármacos , Receptores de Amina Biogénica/metabolismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationship studies on novel non-imidazole, D-amino acid containing ligands of histamine 3 receptors are presented. A-304121 is a D-alanine piperazine amide with high affinity at the rat H(3) receptor.