Abstract
The effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing D(3)R ligands via inclusion of an o-xylenyl motif was examined in this study. Generally, rigidification with an o-xylenyl linker group reduces D(3)R affinity and negatively impacts selectivity versus D(2)R for compounds possessing a 6-methoxy-1,2,3,4,-tetrahydroisoquinolin-7-ol primary pharmacophore group. However, D(3)R affinity appears to be regulated by the primary pharmacophore group and high affinity D(3)R 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 D(3)R selectivity versus the σ(2)R 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) D(3)R ligands. Docking studies revealed that the added phenyl ring moiety interacts with the Cys181 in D(3)R which partially accounts for the strong D(3)R affinity of the ligands.