RESUMEN

Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.

Asunto(s)

Antagonistas de Receptores Adrenérgicos alfa 1/síntesis química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Diseño de Fármacos , Piperazinas/síntesis química , Piperazinas/farmacología , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/metabolismo , Animales , Células CHO , Línea Celular Tumoral , Técnicas de Química Sintética , Clonación Molecular , Cricetinae , Cricetulus , Humanos , Masculino , Simulación del Acoplamiento Molecular , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Piperazinas/química , Piperazinas/metabolismo , Conformación Proteica , Ratas , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/genética , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad