Search for Selective Glua1 Ampa Receptor Antagonists in a Series of Dicationic Compounds

Homologous series of dicationic derivatives based on adamantyl and phenylcyclohexyl fragments in which the cationic groups and the distance between them were varied by using hydrocarbon chains five or six methylene units in length were synthesized. The ability of the dications to block open channels of NMDA and AMPA glutamate receptors was investigated. Pyramidal neurons isolated from the hippocampal CA1 zone were used to study the NMDA channels. Giant cholinergic interneurons of striatum were used in studies of AMPA receptors missing GluA2 subunits. An investigation of the structure-activity relationship of the dications revealed five compounds (IEM-2131, -2132, -2133, -2041, -2297) that surpassed the reference GluA1 AMPA antagonist IEM-1460 in terms of GluA1 AMPA selectivity. IEM-2131, which was an order of magnitude more active than IEM-1460 in AMPA-blocking activity (IC50 = 0.29 and 3 mu M, respectively), showed the maximum AMPA activity and selectivity and had five times better AMPA selectivity (101- and 500-fold, respectively). The clinical prospects of the new GluA1 AMPA blockers were discussed.