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 σ₂ 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 σ₁/σ₂ 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 σ₁/σ₂ selectivity, derived from a higher σ₂ affinity and a lower σ₁ 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 σ₂ receptor binding affinity and selectivity for this active series.