Dataset Information


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 were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.


PROVIDER: S-EPMC4400266 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2013-01-01 | S-EPMC3849818 | BioStudies
1000-01-01 | S-EPMC3904085 | BioStudies
2014-01-01 | S-EPMC4018553 | BioStudies
2013-01-01 | S-EPMC3975045 | BioStudies
2020-01-01 | S-EPMC7050010 | BioStudies
1000-01-01 | S-EPMC4940815 | BioStudies
2017-01-01 | S-EPMC5456073 | BioStudies
2013-01-01 | S-EPMC3880013 | BioStudies
2020-01-01 | S-EPMC7388359 | BioStudies
2017-01-01 | S-EPMC5512122 | BioStudies