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

Kuo Hsien Fan, John R. Lever, Susan Z. Lever

Research output: Contribution to journalArticlepeer-review

Abstract

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 σ12 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 σ12 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.

Original languageEnglish (US)
Pages (from-to)1852-1859
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number6
DOIs
StatePublished - Mar 15 2011
Externally publishedYes

Keywords

  • Aminobutyl-benzamides
  • Sigma receptors
  • Structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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