Imidazo[1,2-b]pyridazines .22. Syntheses of some 2-aryl-3-methoxy-6-(pyridinylmethylthio and pyridinylmethylamino)imidazo[1,2-b]pyridazines and their interaction with central and mitochondrial (peripheral-type) benzodiazepine receptors

2-Aryl-3-methoxy-6-(pyridinylmethylthio and pyridinylmethylamino)imidazo[1,2-b]pyridazines have been prepared and examined as ligands for benzodiazepine receptors. Most were highly effective in displacing [H-3]diazepam from central benzodiazepine receptors present in rat brain membranes but showed little capacity for its displacement from mitochondrial (peripheral-type) benzodiazepine receptors present in rat kidney membranes. For example, 3-methoxy-2-(3',4'-methylenedioxyphenyl)-6-(pyridin-2 ''-ylmethylthio)imidazo[1,2-b]pyridazine had an IC50 value of 1.7 nM for central receptors but gave only 39% displacement at 1000 nM for mitochondrial receptors. Of all the compounds described in this series of papers, 3-methoxy-6-(2'-methoxybenzylamino)-2-(3 '',4 ''-methylenedioxyphenyl)imidazo[1,2-b]pyridazine was the most active in displacing [H-3]diazepam from central receptors (IC50 0.3 nM), and it had a low affinity for mitochondrial receptors (40% displacement of [H-3]diazepam at 1000 nM).