Effects of [(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]alkanoic acids, [(N-alkyl-1-oxo-1H,3H-isoindolin-5-yl)oxy]butanoic acids, and related derivatives on chloride influx in primary astroglial cultures

It has been shown that agents that inhibit chloride influx and therefore lower intracellular chloride levels in a major cell type in cerebral gray matter, the astrocyte, inhibit astrocytic swelling in vitro and in vivo. In our laboratories, 4-[(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]alkanoic acids and related derivatives have been synthesized and tested for ability to lower intracellular astrocytic chloride levels in an established in vitro cultured rat astrocyte model. In general, derivatives with nitrogen substituents such as relatively small alkyl groups are active at 0.1 mM and/or 0.5 mM levels whereas larger substituents such as cyclopentyl and cyclohexyl are less active. Halogen substitution on the aromatic ring did not enhance activity. Derivatives with acid side chains of four carbons demonstrated superior activity to those of two carbons.