Effect of 1‑Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin‑1 Receptor

Selective blockade of the orexin-1 receptor (OX₁) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain’s reward system. We have recently reported a series of tetrahydroisoquinoline-based OX₁ selective antagonists. Aimed at elucidating structure–activity relationship requirements in other regions of the molecule and further enhancing OX₁ potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX₁ receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound <b>73</b> (RTIOX-251) with an apparent dissociation constant (<i>K</i>_e) of 16.1 nM at the OX₁ receptor and >620-fold selectivity over the OX₂ receptor. In vivo, compound <b>73</b> was shown to block the development of locomotor sensitization to cocaine in rats