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 CA-1 region of rat hippocampal slices by the "vibrodissociation" method were voltage-clamped in the whole cell configuration. The currents through NMDA channels were recorded in response to rapid application (solution exchange time <30 ms) of 100 microM aspartate (ASP) in a Mg2+-free solution in the presence of 3 microM glycine. When added to the ASP solution, amantadine as well as other amino-adamantane derivatives (AAD) produced an open-channel blockade of NMDA channels. Membrane hyperpolarization enhanced the AAD 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 blocker (calculated using HyperChem molecular modeling program) and on the blocker's hydrophobicity (calculated according to Hansch and Leo, 1979). The affinity between NMDA channels and AAD diminished with an increase in molecular size and raised with an increase in blocker's hydrophobicity. We propose an empirical equation which describes the dependence of affinity on the size and hydrophobicity of the blocker. The estimated critical diameter of the NMDA channel pore where the AAD blocking site is located proved to be about 17 A.
Sobolevsky
A I
AI
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow. rans@rans.msk.ru
Koshelev
S G
SG
Khodorov
B I
BI
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D004594:Electrophysiology; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007473:Ion Channels / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D000218:Adamantane; D005998:Glycine