Differential inhibition of AE1 and AE2 anion exchangers by oxonol dyes and by novel polyaminosterol analogs of the shark antibiotic squalamine.
Oxonol and polyaminosterol drugs were examined as inhibitors of recombinant mouse AE1 and AE2 anion exchangers expressed in Xenopus laevis oocytes and were compared as inhibitors of AE1-mediated anion flux in red cells and in HL-60 cells that express AE2. The oxonols WW-781, diBA(5)C4, and diBA(3)C4 inhibited HL-60 cell Cl-/Cl- exchange with IC50 values from 1 to 7 microM, 100-1000 times less potent than their IC50 values for red cell Cl-/anion exchange. In Xenopus oocytes, diBA(5)C4 inhibited AE1-mediated Cl- efflux several hundred times more potently than that mediated by AE2. Several novel squalamine-related polyaminosterols were also evaluated as anion exchange inhibitors. In contrast to diBA(5)C4, polyaminosterol 1361 inhibited oocyte-expressed AE2 8-fold more potently than AE1 (IC50 0.6 versus 5.2 microM). The 3-fold less potent desulfo-analog, 1360, showed similar preference for AE2. It was found that 1361 also partially inhibited Cl- efflux from red cells, whereas neither polyaminosterol inhibited Cl efflux from HL60 cells. Thus, the oxonol diBA(5)C4 is >100-fold more potent as an inhibitor of AE1 than of AE2, whereas the polyaminosterols 1360 and 1361 are 8-fold more potent as inhibitors of AE2 than of AE1. Assay conditions and cell type influenced IC50 values for both classes of compounds.
Alper
S L
SL
Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Chernova
M N
MN
Williams
J
J
Zasloff
M
M
Law
F Y
FY
Knauf
P A
PA
D000818:Animals; D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017920:Antiporters / Q000037:antagonists & inhibitors*; D001463:Barbiturates / Q000494:pharmacology; D027963:Chloride-Bicarbonate Antiporters; D002777:Cholestanols / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes; D005456:Fluorescent Dyes / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D064606:SLC4A Proteins; D012754:Sharks / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology
D027321:Anion Transport Proteins; D000900:Anti-Bacterial Agents; D017920:Antiporters; D001463:Barbiturates; D027963:Chloride-Bicarbonate Antiporters; D002777:Cholestanols; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D007555:Isoxazoles; C097374:KV 1360; D008565:Membrane Proteins; D011073:Polyamines; D064606:SLC4A Proteins; C052795:bis(1,3-dibutylbarbiturate)trimethine oxonol; C079655:squalamine