Different arrangement of hydrophobic and nucleophilic components of channel binding sites in N-methyl- d-aspartate and AMPA receptors of rat brain is revealed by channel blockade

• Published in: Neuroscience letters Vol. 291; no. 2; pp. 101 - 104
• Main Authors: Bolshakov, K.V, Tikhonov, D.B, Gmiro, V.E, Magazanik, L.G
• Format: Journal Article
• Language: English; Russian
• Published: Shannon Elsevier Ireland Ltd 15.09.2000; Elsevier
• Subjects: AMPA receptor; Animals; Binding Sites - drug effects; Brain Chemistry - drug effects; Calcium Channel Blockers - pharmacology; Calcium Channels - metabolism; Channel block; Channel structure; Hippocampus - chemistry; Membrane Potentials - drug effects; N-methyl- d-aspartate receptor; Patch-Clamp Techniques; Protein Structure, Tertiary; Rats; Receptors, AMPA - chemistry; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Structure-Activity Relationship; Structure-activity relationships; AMPA receptor; Structure-activity relationships; N-methyl- d-aspartate receptor; Channel structure; Channel block
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/S0304-3940(00)01386-0

In order to investigate the topography of the channel binding site in (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl- d-aspartate (NMDA) types of glutamate receptors, we have compared the blocking actions of mono- and dicationic derivatives of adamantane and phenylcyclohexyl. The potencies of dicationic derivatives to block AMPA receptor channels are about 1000 times higher than those of monocationic ones, whereas NMDA receptors are equally sensitive to both mono- and dicationic derivatives. The dependence of the activity of dicationic compounds on the length of the polymethylene chain between ammonium groups has a pronounced maximum for AMPA receptor channel block. For NMDA receptor channel dicationic compounds with various internitrogen distances produce similar blocking effects. The results show that hydrophobic and nucleophilic components of the binding site are located close to each other in the NMDA receptor channel but are separated by ∼10 Å in the AMPA receptor channel.