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.
Waller
C L
CL
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360.
Wyrick
S D
SD
Park
H M
HM
Kemp
W E
WE
Smith
F T
FT
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D017920:Antiporters / Q000187:drug effects / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000378:metabolism; D005665:Furosemide / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters
D017920:Antiporters; D001639:Bicarbonates; D002352:Carrier Proteins; D018118:Chloride Channels; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D007211:Indoles; D028021:Sodium-Potassium-Chloride Symporters; D005665:Furosemide; D012964:Sodium; D011188:Potassium