RESUMEN

A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists.

Asunto(s)

Amnesia/tratamiento farmacológico , Indoles/farmacología , Piperazinas/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sulfonas/farmacología , Amnesia/inducido químicamente , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Modelos Moleculares , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Escopolamina , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/química