Imidazo[1,2-b]Pyridazines. VI. Syntheses and Central Nervous System Activities of Some 6-(Alkoxy- and Methylthio-phenoxy and Methoxybenzylthio)-3-methoxy-2-phenyl(substituted phenyl and pyridinyl)Imidazo[1,2-b]pyridazines

Abstract

Series of 6-( alkoxy - and methylthio-phenoxy )-2-phenyl(substituted phenyl and pyridiny1)imidazo[l,2-b]pyridazines and 3-methoxy-6-( methoxybenzylthio )-2-phenyl(substituted phenyl and pyridinyl ) imidazo[l,2-b]pyridazines have been prepared and subsequently tested for their ability to inhibit GABA-stimulated ³H-diazepam binding to rat brain plasma membranes.

The 6( alkoxy- and methylthio-phenoxy ) and 6-( methoxybenzylthio) compounds were much more effective in the displacement studies than the parent 6-phenoxy or 6-benzylthio compounds respectively.

3-Methoxy-6-(2′-methoxyphenoxy)-2-phenylimidazo[l,2-b]pyridazine (GBLD-167, IC₅₀ 70 nm) was 16 times more effective than its 3-methoxy-6-phenoxy analogue (GBLD-163, IC₅₀ 1120 nM ) and the 3-methoxy-6-(2₁-methoxybenzylthio)-2-phenyl compound (GELD-214, 1C₅₀ 9 nM ) was two and a half times more active than its 6-benzylthio-3-methoxy analogue (GBLD-137, IC₅₀ 22 nM ). The most active member of the 6-phenoxy series was the 2-(41-fluorophenyl)-3-methoxy-6- (2″-methoxyphenoxy) compound (GBLD-255, IC₅₀ 30 nM ) and, within the 6-benzylthio series, the 2-(4′-fluorophenyl, 3′-aminophenyl, and pyridin-31-yl)-3-methoxy-6-(3″-methoxybenzylthio) compounds (GBLD-233, 301 and 296) all gave IC₅₀ 5 nM.

A Hansch -type analysis of the results for these two closely related series of compounds indicates that electron-donating substituents in 2-(para substituted phenyl) derivatives favour binding, but bulky substituents hinder this effect.