STRUCTURE AND INTERACTION OF INHIBITORS WITH THE TEA H-BORDER MEMBRANES( EXCHANGER OF RABBIT RENAL BRUSH)

The renal secretion of organic cations (OCs) involves a carrier-mediat ed exchange of OC for H+ in the luminal membrane of proximal cells. To assess the influence of chemical structure on the interaction of pote ntial substrates with this process we examined the effect of a series of quaternary ammonium compounds on the transport of the OC tetraethyl ammonium (TEA) in a preparation of isolated renal brush-border membran e vesicles. Apparent inhibitory potency varied over a factor of 10(4), as expressed in inhibitor coefficients (K-i(TEA)) whose approximate v alues ranged from 0.5 mu M to 5 mM. The poorest inhibitors of TEA/H+ e xchange were those molecules with carboxyl or hydroxyl residues, where as the addition of methylene groups to a parent molecule tended to inc rease inhibitory potency. A plot of apparent K-i(TEA) versus calculate d octanol:water partition coefficient (expressed in terms of a relativ e lipophilicity factor) showed a clear correlation between these two p arameters, although there was considerable variability between apparen t lipophilicity and K-i(TEA) for molecules with very different parent structures. For select groups of molecules with similar parent structu res (e.g., the n-tetraalkylammoniums or the 4-phenylpyridinium, 3-phen ylpyridinium, and quinolinium compounds) the correlation between calcu lated lipophilicity and apparent K-i(TEA) was more marked. However, ev en within these groups of closely related parent structures, there app eared to be subtle, but systematic, variations in inhibitory potency t hat may have been related to the influence of steric factors on the bi nding of inhibitors to the TEA/H+ exchanger. We conclude that the lipo philic nature of a quaternary ammonium compound represents the predomi nant factor in the binding to, and subsequent inhibition of, luminal T EA/H+ exchange. Specific steric factors may influence the binding of s ubstrate to the exchanger, but play a secondary role in this interacti on.