Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor

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

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