Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor

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

Perrey, D. A., German, N., Gilmour, B., Li, J. X., 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. DOI: 10.1021/jm400720h