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Substituted tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor.


ABSTRACT: 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.

SUBMITTER: Perrey DA 

PROVIDER: S-EPMC3849818 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Substituted tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor.

Perrey David A DA   German Nadezhda A NA   Gilmour Brian P BP   Li Jun-Xu JX   Harris Danni L DL   Thomas Brian F BF   Zhang Yanan Y  

Journal of medicinal chemistry 20130826 17


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. Pyridylmethy  ...[more]

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