New tetrahydroisoquinoline-based DR ligands with an o-xylenyl linker motif.

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