Effect of structural modification in the amine portion of substituted aminobutyl-benzamides as ligands for binding σ₁ and σ₂ receptors

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• 作者：Kuo-Hsien Fan^a ; John R. Lever^b ; ^c ; ^d ; Susan Z. Lever^a ; ^e ; ^{levers@missouri.edu}
• 关键词：Sigma receptors ; Structure– ; activity relationships ; Aminobutyl-benzamides
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 March 2011
• 年：2011
• 卷：19
• 期：6
• 页码：1852-1859
• 全文大小：604 K

文摘

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide (1) is one of the most potent and selective σ₂ receptor ligands reported to date. A series of new analogs, where the amine ring fused to the aromatic ring was varied in size (5–7) and the location of the nitrogen in this ring was modified, has been synthesized and assessed for their σ₁/σ₂ binding affinity and selectivity. The binding affinity of an open-chained variant of 1 was also evaluated. Only the five-membered ring congener of 1 displayed a higher σ₁/σ₂ selectivity, derived from a higher σ₂ affinity and a lower σ₁ affinity. Positioning the nitrogen adjacent to the aromatic ring in the five-membered and six-membered ring congeners dramatically decreased affinity for both subtypes. Thus, location of the nitrogen within a constrained ring is confirmed to be key to the exceptional σ₂ receptor binding affinity and selectivity for this active series.