Lishko P. The role of hydrophobic interactions in the modulation of NMDA receptor-operated ionic channels in rat hippocampal neurons.

The dissertation is devoted to the investigation of the effects of the derivatives of imidazole-4,5- and pyrazole-3,4- dicarboxylic acids and of a new benzopyranone compound anseculine hydrochloride ( KA-672), on the NMDA receptor-operated ionic channels. In this study the action of compounds on the NMDA receptors was examined by applying patch clamp techniques to the enzymatically isolated rat hippocampal neurons. It has been found that KA- 672.HCl is a new uncompetitive NMDA receptor operated channel-blocker with IC50 = 20 ± 7 mM. The screening of imidazole-4,5- and pyrazole-3,4- dicarboxylic acids derivatives allows to modernize the concept of structure/function relationship for the glutamate receptors antagonists. It has been proposed that in the glutamate-recognition site of NMDA receptor there is a lipophylic area near the binding point for amino group. Liphophylic substituent of imidazole- or pyrazole- derivatives can directly interact with it. This interaction leads to a decrease in the agonis tic properties and to the appearance of the antagonistic ones. The investigated derivatives are a new class of excitatory amino acids receptor ligands, in which the increase in lipophily can evoke a decrease of agonistic and increase of antagonistic NMDA activity.