Effects of [(N-alkyl-1,3-dihydro-1-oxoisoindolin-5-yl)oxy]alkanoic acids on chloride transport in primary astroglial cultures.

It has been demonstrated that agents which inhibit chloride influx and, therefore, lower intracellular chloride levels in the astrocyte, a major cell type in the cerebral gray matter, inhibit astrocytic swelling in vitro and in vivo. Herein, we report additional examples of a series of [(N-alkyl-1,3-dihydro-1-oxoisoindolin-5-yl)oxy]alkanoic acids and their effects upon ion transport in primary rat astrocyte cultures. The 4-chloro-substituted 1-oxoisoindolines demonstrated superior astrocytic chloride influx inhibitory activity as compared to the 6-chloro and non-chlorinated analogs. The four-carbon acid side chain derivatives were more active than the three- and two-carbon analogs. The pharmacological profile of these compounds was examined with respect to inhibition of the Cl(-)-Cl-/Cl(-)-HCO3- anion exchanger and Na(+)-K(+)-2Cl- cotransport mechanisms in glia, and the compounds were found to exhibit a similar profile to that of furosemide by inhibiting both transporters.