IEM 1754 dihydrobroMide

IEM 1754 dihydrobroMide is a selective AMPA/kainate receptor blockers for GluR1 and GluR3 with IC50 of 6 μM.

Voltage-dependent block of native AMPA receptor channels by dicationic compounds.[Pubmed:10694232]

Br J Pharmacol. 2000 Jan;129(2):265-74.

1. 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. 2. 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. 3. 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. 4. 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.

Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives.[Pubmed:9457643]

J Physiol. 1997 Dec 15;505 ( Pt 3):655-63.

1. The effects of two adamantane derivatives, 1-trimethylammonio-5-(1-adamantane-methyl-ammoniopentane dibromide) (IEM-1460) and 1-ammonio-5-(1-adamantane-methylammoniopentane dibromide) (IEM-1754) on kainate-induced currents were studied in Xenopus oocytes expressing recombinant ionotropic glutamate receptors and in freshly isolated neurones from rat hippocampal slices. 2. The adamantane derivatives caused use- and voltage-dependent block of open channels of recombinant AMPA receptors. This antagonism was dependent on receptor subunit composition; channels gated by recombinant, homomeric GluR1 and GluR3 receptors exhibited a higher sensitivity to block than those gated by receptors containing edited GluR2 subunits. In the former cases, IEM-1460 had an IC50 of 1.6 microM at a holding potential (Vh) of -80 mV and IEM-1754 was 3.8 times less potent than IEM-1460. In contrast, 100 microM IEM-1460 inhibited responses to 100 microM kainate of receptors containing edited GluR2 subunits by only 7.8 +/- 2.4% (n = 5 oocytes at a Vh of -80 mV. 3. Native AMPA/kainate receptors in isolated hippocampal cells were inhibited by adamantane derivatives in a use- and voltage-dependent manner. This antagonism was dependent on cell type: pyramidal neurones were less sensitive to IEM-1460 (IC50 = 1617 microM at Vh = -80 mV) than interneurones (IC50 = 1.6 microM at Vh = -80 mV). IEM-1460 and IEM-1754 were equipotent when applied to pyramidal neurones, but IEM-1754 was less potent (approximately 3 times) than IEM-1460 when applied to interneurones. 4. It is concluded that the presence of the edited GluR2 subunit in recombinant AMPA receptors and native AMPA/kainate receptors inhibits channel block by organic cations and that adamantane derivatives are potentially valuable tools for identifying classes of AMPA/kainate receptors and their roles in synaptic transmission.