Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor.

ABSTRACT: 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 we

SUBMITTER: Perrey DA 

PROVIDER: S-EPMC4400266 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature