RESUMEN
We have previously described a series of antagonists that showed high potency and selectivity for the NK(1) receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here we show that alteration of the 2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK(1) receptor affinity for the various conformational forms has facilitated the development of a detailed NK(1) pharmacophore model.
Asunto(s)
Naftalenos/síntesis química , Antagonistas del Receptor de Neuroquinina-1 , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular Tumoral , Perros , Gerbillinae , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Conejos , Ensayo de Unión Radioligante , Receptores de Neuroquinina-1/química , Receptores de Neuroquinina-1/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.
