期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 19, 期 6, 页码 1852-1859出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.02.006
关键词
Sigma receptors; Structure-activity relationships; Aminobutyl-benzamides
资金
- National Institute on Drug Abuse [DA028477]
- National Science Foundation (US) [CHE-89-08304, CHE-95-31247, CHE-92-2183526]
- National Institutes of Health (US) [1S10RR11962-01]
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(2) 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 sigma(1)/sigma(2) 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 sigma(1)/sigma(2) selectivity, derived from a higher sigma(2) affinity and a lower sigma(1) 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 sigma(2) receptor binding affinity and selectivity for this active series. (C) 2011 Elsevier Ltd. All rights reserved.
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