RESUMEN
The synthesis and in vivo anti-inflammatory activity of a series of pseudopterosin analogues are presented. Synthetic tricyclic catechol aglycons with different substitution patterns were monofucosylated or -xylosylated. Anti-inflammatory activity was conserved over a wide range of structural modifications. The most active synthetic compound 33 reduced phorbol myristate acetate (PMA)-induced inflammation in the mouse ear by 72% at 50 µg/ear. This corresponds to 80% of the activity of natural pseudopterosin A.
Asunto(s)
Antiinflamatorios/síntesis química , Diterpenos/química , Galactósidos/síntesis química , Glicósidos/química , Fenalenos/síntesis química , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Catecoles/química , Diterpenos/síntesis química , Diterpenos/uso terapéutico , Galactósidos/química , Galactósidos/uso terapéutico , Glicósidos/síntesis química , Glicósidos/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Ratones , Fenalenos/química , Fenalenos/uso terapéutico , Relación Estructura-Actividad , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.