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

A series of 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. Location of the nitrogen within a constrained ring is confirme... Full description

Journal Title: Bioorganic & Medicinal Chemistry 15 March 2011, Vol.19(6), pp.1852-1859
Main Author: Fan, Kuo-Hsien
Other Authors: Lever, John R , Lever, Susan Z
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0968-0896 ; E-ISSN: 1464-3391 ; DOI: 10.1016/j.bmc.2011.02.006
Link: https://www.sciencedirect.com/science/article/pii/S0968089611001143
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title: Effect of structural modification in the amine portion of substituted aminobutyl-benzamides as ligands for binding σ1 and σ2 receptors
format: Article
creator:
  • Fan, Kuo-Hsien
  • Lever, John R
  • Lever, Susan Z
subjects:
  • Sigma Receptors
  • Structure–Activity Relationships
  • Aminobutyl-Benzamides
  • Medicine
  • Chemistry
  • Anatomy & Physiology
ispartof: Bioorganic & Medicinal Chemistry, 15 March 2011, Vol.19(6), pp.1852-1859
description: A series of 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. 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. 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.
language: eng
source:
identifier: ISSN: 0968-0896 ; E-ISSN: 1464-3391 ; DOI: 10.1016/j.bmc.2011.02.006
fulltext: fulltext
issn:
  • 0968-0896
  • 09680896
  • 1464-3391
  • 14643391
url: Link


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titleEffect of structural modification in the amine portion of substituted aminobutyl-benzamides as ligands for binding σ1 and σ2 receptors
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descriptionA series of 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. 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. 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.
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