Synthesis and in vitro evaluation of tetrahydroisoquinolinyl benzamides as ligands for [sigma] receptors
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 [sigma] sub(2) receptor ligands reported to date. Previous structure- activity relationship studies of such tetrahydroisoquinolinyl benzamides have focused on t...
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Published in | Bioorganic & medicinal chemistry letters Vol. 17; no. 9; pp. 2594 - 2597 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
01.05.2007
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Online Access | Get full text |
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Summary: | 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 [sigma] sub(2) receptor ligands reported to date. Previous structure- activity relationship studies of such tetrahydroisoquinolinyl benzamides have focused on the linker that connects the ring systems and the effects of benzamide ring substituents. The present study explores the effects of fusing methylene-, ethylene-, and propylenedioxy rings onto the tetrahydroisoquinoline in place of the two methoxy groups. These modifications decreased [sigma] sub(2) affinity by 8- to 12-fold, with no major differences noted with ring size. By contrast, the methylenedioxy analog showed a 10-fold greater [sigma] sub(1) affinity than 1, and progressively lower [sigma] sub(1) affinities were then noted with increasing ring size. We also opened the tetrahydroisoquinoline ring of 1 to study the effects of greater conformational fluidity on [sigma] receptor binding. The [sigma] sub(2) affinity of the open-ring compound decreased by 1700-fold, while [sigma] sub(1) affinity was not changed. Thus, a constrained tetrahydroisoquinoline ring system is key to the exceptional [sigma] sub(2) receptor binding affinity and selectivity of this active series. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2 |
ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2007.02.005 |