Syntheses, pharmacological evaluation and molecular modelling of substituted 6-alkoxyimidazo[1,2-b]pyridazines as new ligands for the benzodiazepine receptor

P. W. Harrison, G. B. Barlin, L. P. Davies, S. J. Ireland, P. Mátyus, M. G. Wong

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

A series of 2,3-disubsdtuted-6-alkoxyimidazo[1,2-b]pyridazines has been synthesized and evaluated for in vitro affinity for the benzodiazepine receptor (BZR). 3-(Benzamidomethyl or substituted benzamidomethyl)-6-methoxy-2-(3,4-methylenedioxyphenyl) imidazo[1,2-b]pyridazines were found to be the most potent BZR ligands (eg, 4a, IC50 7 nM; 4e, IC50 14 nM; 4v, IC50 8 nM). Imidazo[1,2-b]pyridazines unsubstituted in the 3-position, or containing bulkier alkoxy groups in the 6-position, were found to bind less strongly to the BZR. selected compounds from the series were identified from in vitro GABA-shift experiments as BZR agonists. Molecular modelling has been employed to identify the common pharmacophoric points of lipophilic and hydrogen bonding, ligand-receptor interaction and areas of steric hindrance for these substituted imidazo[1,2-b]pyridazines at the BZR.

Original languageEnglish
Pages (from-to)651-662
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume31
Issue number9
DOIs
Publication statusPublished - Jan 1 1996

Keywords

  • Benzodiazepine receptor
  • Molecular modelling
  • Structure-activity relationship
  • imidazo[1,2-b]pyridazine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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