Syntheses, pharmacological evaluation and molecular modelling of substituted 6-alkoxyimidazopyridazines as new ligands for the benzodiazepine receptor

Article abstract of DOI:10.1016/0223-5234(96)85873-9

A series of 2,3-disubstituted-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 wereidentified 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. - Keywords: imidazo<1,2-b>pyridazine; benzodiazepine receptor; structure-activity relationship; molecullar modelling