SYNTHESES, PHARMACOLOGICAL EVALUATION AND MOLECULAR MODELING OF SUBSTITUTED 6-ALKOXYIMIDAZO[1,2-B]PYRIDAZINES AS NEW LIGANDS FOR THE BENZODIAZEPINE RECEPTOR

A series of 2,3-disubstituted-6-alkoxyimidazo[1,2-b] has been synthesi zed and evaluated for in vitro affinity for the benzodiazepine recepto r (BZR). 3-(Benzamidomethyl or substituted 3,4-methylenedioxyphenyl)im idazo[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]pyrid azines unsubstituted in the 3-position, or containing builder alkoxy g roups 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 employ ed to identify the common pharmacophoric points of lipophilic and hydr ogen bonding, ligand-receptor interaction and areas of steric hindranc e for these substituted imidazo[1,2-b]pyridazines at the BZR.