Synthesis and in vitro evaluation of tetrahydroisoquinolinyl benzamides as ligands for σ 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. Previous structure-activity relationship studies of such tetrahydroisoquinolinyl benzamides have focused on the linker that connects the ring systems and the effects of benzamide ring substituents. The present study explores the effects of fusing methylene-, ethylene-, and propylenedioxy rings onto the tetrahydroisoquinoline in place of the two methoxy groups. These modifications decreased σ₂ affinity by 8- to 12-fold, with no major differences noted with ring size. By contrast, the methylenedioxy analog showed a 10-fold greater σ₁ affinity than 1, and progressively lower σ₁ affinities were then noted with increasing ring size. We also opened the tetrahydroisoquinoline ring of 1 to study the effects of greater conformational fluidity on σ receptor binding. The σ₂ affinity of the open-ring compound decreased by 1700-fold, while σ₁ affinity was not changed. Thus, a constrained tetrahydroisoquinoline ring system is key to the exceptional σ₂ receptor binding affinity and selectivity of this active series.