• Article

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 73 (RTIOX-251) with an apparent dissociation constant (K-e) 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.

Citation

Perrey, D. A., German, N. A., Decker, A. M., Thorn, D., Li, J-X., Gilmour, B. P., ... Zhang, Y. (2015). Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor. ACS Chemical Neuroscience, 6(4), 599-614. DOI: 10.1021/cn500330v

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