Macromolecular conjugates of transport inhibitors : new tools for probing topography of anion transport proteins

Macromolecular-conjugated, water-soluble, membrane-impermeant compounds were designed and assessed as topological probes for chloride-transporting agencies. The novel compounds were derivatives of either disulfonic stilbene (DS) and benzylaminoethylsulfonate (BS), "classical" inhibitors of erythrocyte chloride-bicarbonate exchange, or of phenylanthranilates (PA), high-affinity blockers of epithelial chloride channels. Covalent reactive derivatives of various DS, BS, and PA were synthesized and coupled either directly to polyethylene glycol or via spacer arms of different lengths to dextrans. The macromolecular conjugates were demonstrably inhibitory to red blood cell anion exchange when the ligands were appropriately coupled: inhibitory efficacy strongly depended on the chemical structure of the coupled ligand and the spacer length between the inhibitory moiety and the macromolecule. Mechanistic studies indicated that impermeant DS and PA derivatives acted exofacially on sites, which although different in...