New tetrahydroisoquinoline-based D₃R ligands with an o-xylenyl linker motif

The effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing D₃R ligands via inclusion of an o-xylenyl motif was examined in this study. Generally, rigidification with an o-xylenyl linker group reduces D₃R affinity and negatively impacts selectivity versus D₂R for compounds possessing a 6-methoxy-1,2,3,4,-tetrahydroisoquinolin-7-ol primary pharmacophore group. However, D₃R affinity appears to be regulated by the primary pharmacophore group and high affinity D₃R ligands with 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline primary pharmacophore groups were identified. The results of this study also indicate that D₃R selectivity versus the σ₂R is dictated by the benzamide secondary pharmacophore group, this being facilitated with 4-substituted benzamides. Compounds 5s and 5t were identified as high affinity (K_i < 4 nM) D₃R ligands. Docking studies revealed that the added phenyl ring moiety interacts with the Cys181 in D₃R which partially accounts for the strong D₃R affinity of the ligands.