Design of antagonists for NMDA and AMPA receptors.

Determinants of antagonism of NMDA and calcium permeable AMPA receptor channels by organic cations were studied using several homologous series of mono- and dicationic derivatives of adamantane, phenylcyclohexyl, triphenylmethane, diphenylmethane. Antagonism by these drugs was studied on native receptors of isolated rat brain neurons and on recombinant GluR1 receptors expressed by Xenopus oocytes. The major action of these compounds was on the open channel, although minor competitive or closed channel antagonism cannot be ruled out. Analysis of structure-activity relationships suggests that all organic monocations are selective antagonists of NMDA receptors. Compounds exhibiting trapping block are more potent than those exhibiting weakly-trapping block. AMPA and NMDA receptor channels are blocked by dicationic organic compounds, the former requiring a certain distance between the hydrophobic moiety and the terminal charged group. Variations of their terminal ammonium group demonstrated that trimethylammonium derivatives are the most potent antagonists of AMPA receptors, whereas the terminal amino group is optimal for block of NMDA receptors. Based on the action of 38 compounds, topographical models of the binding sites of these compounds on NMDA and AMPA receptor channels are presented. These models will help to design channel-blocking drugs with defined potency and selectivity of action.