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.