Effect of structural modification in the amine portion of substituted aminobutyl-benzamides as ligands for binding σ1 and σ2 receptors

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide (1) is one of the most potent and selective Ï2 receptor ligands reported to date. A series of new analogs, where the amine ring fused to the aromatic ring was varied in size (5–7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their Ï1/Ï2 binding affinity and selectivity. The binding affinity of an open-chained variant of 1 was also evaluated. Only the five-membered ring congener of 1 displayed a higher Ï1/Ï2 selectivity, derived from a higher Ï2 affinity and a lower Ï1 affinity. Positioning the nitrogen adjacent to the aromatic ring in the five-membered and six-membered ring congeners dramatically decreased affinity for both subtypes. Thus, location of the nitrogen within a constrained ring is confirmed to be key to the exceptional Ï2 receptor binding affinity and selectivity for this active series. A series of analogs, where the amine ring fused to the aromatic ring was varied in size (5–7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their Ï1/Ï2 binding affinity and selectivity. Location of the nitrogen within a constrained ring is confirmed to be key to the exceptional Ï2 receptor binding affinity and selectivity for this active series.