Substrate structure exerts little effect on binding to the organic cation/H⁺ exchanger of rabbit renal luminal membranes

The kidney secretes organic cations (OCs) and the active step involves OC/H⁺ exchange in the luminal membrane of proximal cells. Although lipophilicity is an important criterion for binding of substrates to this transporter (Pflügers Arch, 429:313, 1995), the steric influence of substrate structure is unclear. We examined this issue by measuring the inhibition of OC/H⁺ exchange produced by structurally-related OCs. OC/H⁺ exchange was determined by measuring transport of [¹⁴C]tetraethylammonium (TEA) in brush-border membranes from renal cortex. Transport was measured in the presence of a pH gradient (pH_in 6.0; pH_out 7.5) to maximize TEA/H⁺ exchange. We tested the hypothesis that a systematic shift of molecular mass, from a longitudinal to latitudinal axis (relative to a fixed cationic 'nucleus'), systematically influences the inhibitory effectiveness of our test agents: a series of 4-phenyl and 3-phenyl pyridinium and quinolinium compounds. The 'R' groups on the quaternary nitrogen ranged from a phenyl moiety (most lipophilic) to a -CH₂-CH₂OH moiety (least lipophilic). Inhibitory constants (apparent K_is) for these compounds ranged from ∼1 μM to ∼50 μM. There was a strong correlation between lipophilicity of each compound and its inhibitory effectiveness. There was, however, no clear correlation between longitudinal vs. latitudinal distribution of steric mass and the inhibitory effectiveness of the test substrates. We conclude that steric factors have comparatively little effect on binding of substrates to the renal OC/H⁺ exchanger.