Studies of the structure of glutamate receptor ion channels and the mechanisms of their blockade by organic cations.
The structural determinants for blockade of the AMPA and NMDA subtypes of glutamate receptors were studied by analysis of structural-functional relationships in a series of mono- and dicationic compounds. The results showed that the hydrophobic and nucleophilic components of the blocker binding sites are located close to each other in the channel of the NMDA receptor, while they are spatially distant in the channel of the AMPA receptor. Molecular mechanical methods were used to construct models of these channels satisfying these topographic criteria and providing adequate descriptions of the binding of the channel blockers. According to the models, binding of blockers to the NMDA channel occurs in the selective filter of the channel (the N/Q/R site). The nucleophilic region of the AMPA channel is formed by the oxygen atoms of glycine residues in position +2 relative to the selective filter. Identification of the major relationships between the molecular structure of the ion channels of these glutamate receptor subtypes and their blockade by organic cations allows the further synthesis of AMPA and NMDA channel blockers with specified levels of activity and selectivity to be directed.
Magazanik
L G
LG
I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 M. Torez Prospekt, 194223 St. Petersburg, Russia.
Tikhonov
D B
DB
Bol'shakov
K V
KV
Gmiro
V E
VE
Buldakova
S L
SL
Samoilova
M V
MV
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000547:Amantadine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002412:Cations / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000145:classification; D008954:Models, Biological; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology
D002412:Cations; D018691:Excitatory Amino Acid Antagonists; C110702:IEM 1460; C092754:IEM 1754; D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine; D000218:Adamantane