Imidazo[1,2-b]pyridazines. XXII. 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

Abstract

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 [³H]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 [³H]diazepam from central receptors (IC₅₀ 0·3 nM), and it had a low affinity for mitochondrial receptors (40% displacement of [³H]diazepam at 1000 nM).