• Article

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

Selective antagonism of the orexin 1 (OX1) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure-activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10c, Ke=23.7nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26a, Ke=427nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates

Citation

Perrey, DA., Decker, A., Li, JX., Gilmour, B., Thomas, B., Harris, D., ... Zhang, Y. (2015). The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor. Bioorganic and Medicinal Chemistry, 23(17), 5709-5724. https://doi.org/10.1016/j.bmc.2015.07.013

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