Molecular size and hydrophobicity as factors which determine the efficacy of the blocking action of amino-adamantane derivatives on NMDA channels

Neurons isolated from the CAI region of rat hippocampal slices by the "vibr odissociation'' method were voltage-clamped in the whole cell configuration . The currents through NMDB channels were recorded in response to rapid app lication (solution exchange time < 39 ms) of 100 mu M aspartate (ASP) in a Mg2+-free solution in the presence of 3 mu M glycine, When added to the ASP solution, amantadine as well as other amino-adamantane derivatives (AAD) p roduced an open-channel blockade of NMDB channels. Membrane hyperpolarizati on enhanced the AAI) block. The affinity between NMDA channels and AAD was different for various AAD. The analysis of the experimental data led us to conclude that this affinity depended both on the molecular size of the bloc ker (calculated using HyperChem molecular modeling program) and on the bloc ker's hydrophobicity (calculated according to Hansch and Lee, 1979). The af finity between NMDA channels and AAD diminished with an increase in the mol ecular size and raised with an increase in the blocker's hydrophobicity. We propose an empirical equation which describes the affinity dependence on t he size and hydrophobicity of the blocker. The estimated critical diameter of the NMDA channel pore where the AAD blocking site is located proved to b e about 17 Angstrom.