The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

Selective antagonism of the orexin 1 (OX₁) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure-activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX₁, indicating that the 7-position is important for OX₁ antagonism (10c, K_e = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26a, K_e = 427 nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX₁ receptor are competitive antagonists with slow dissociation rates.