Asunto(s)
Cultura , Judíos , Psicología del Adolescente , Religión y Psicología , Adolescente , Adulto , Actitud , Niño , Desarrollo Infantil , Preescolar , Conflicto Psicológico , Femenino , Humanos , Identificación Psicológica , Relaciones Interpersonales , Judaísmo , Masculino , Matrimonio , Trastornos Mentales/terapia , Persona de Mediana Edad , Personalidad , Teoría Psicoanalítica , Conducta Social , Valores Sociales , Estados UnidosRESUMEN
Production of interleukin-1 and tumour necrosis factor from stimulated human monocytes is inhibited by a new series of pyridinyl-imidazole compounds. Using radiolabelled and radio-photoaffinity-labelled chemical probes, the target of these compounds was identified as a pair of closely related mitogen-activated protein kinase homologues, termed CSBPs. Binding of the pyridinyl-imidazole compounds inhibited CSBP kinase activity and could be directly correlated with their ability to inhibit cytokine production, suggesting that the CSBPs are critical for cytokine production.
Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Citocinas/biosíntesis , Mediadores de Inflamación , Proteínas Quinasas Activadas por Mitógenos , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Línea Celular , Cromosomas Humanos Par 6 , Clonación Molecular , Citocinas/antagonistas & inhibidores , ADN Complementario , Humanos , Imidazoles/farmacología , Interleucina-1/biosíntesis , Datos de Secuencia Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fragmentos de Péptidos , Piridinas/farmacología , Ensayo de Unión Radioligante , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKC alpha and ERK kinase activity is observed.