Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor

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• 作者：David A. Perrey ; Nadezhda A. German ; Brian P. Gilmour ; Jun-Xu Li ; Danni L. Harris ; Brian F. Thomas ; Yanan Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6901-6916
• 全文大小：624K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.