Voltage‐dependent block of native AMPA receptor channels by dicationic compounds

The kinetics of open channel block of GluR2‐containing and GluR2‐lacking AMPA receptors (AMPAR) by dicationic compounds (IEM‐1460, IEM‐1754, and IEM‐1925) have been studied in rat hippocampal neurones using whole‐cell patch clamp recording and concentration‐jump techniques. Neurones were isolated from hippocampal slices by vibrodissociation. The dicationic compounds were approximately 100–200 times more potent as blockers of GluR2‐lacking AMPAR than as blockers of GluR2‐containing AMPAR. The subunit specificity of channel block is determined by the blocking rate constant of a dicationic compound, whereas differences in unblocking rate constants account for differences in potency. Hyperpolarization may decrease the block produced by IEM‐1460 and IEM‐1754 block due to the voltage‐dependence of the unblocking rate constants for these compounds. This suggests that dicationic compounds permeate the AMPAR channel at negative membrane potentials. The effect was particularly apparent for GluR2‐lacking AMPAR. These findings indicate that the presence of GluR2‐subunit(s) in AMPAR hinders the binding of the cationic compounds and their permeation through the channel. The most potent compound tested was IEM‐1925. The presence of a phenylcyclohexyl moiety instead of an adamantane moiety, as in IEM‐1460 and IEM1754, is probably responsible for the higher potency of IEM‐1925. Dicationic compounds are important not only as pharmacological tools, but also as templates for the synthesis of new selective AMPAR blockers which may be potential therapeutic agents.British Journal of Pharmacology (2000) 129 , 265–274; doi: 10.1038/sj.bjp.0703043