Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats
Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor
Perrey, DA., German, N., Gilmour, B., Li, JX., Harris, D., Thomas, B., & Zhang, Y. (2013). Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor. Journal of Medicinal Chemistry, 56(17), 6901-6916. https://doi.org/10.1021/jm400720h
Abstract
Publications Info
To contact an RTI author, request a report, or for additional information about publications by our experts, send us your request.
Meet the Experts
View All ExpertsRecent Publications
Article
The daily association between affect and alcohol use: A meta-analysis of individual participant data
Article
The use of patient experience feedback in rehabilitation quality improvement and codesign activities
Article
Protection of forest ecosystems in the eastern United States from elevated atmospheric deposition of sulfur and nitrogen
Article