IEM 1460

[IEM-1460 and spermine potentiate analgesic effect of fentanyl and dipyrone in rats].[Pubmed:25464766]

Ross Fiziol Zh Im I M Sechenova. 2013 Dec;99(12):1361-5.

Intramuscular (i. m.) administration in the minimum effective dose (MED) of central analgesics of fentanyl and dipyrone, polyamine agonist spermine and also IEM-1460 (IEM-1460 is AMPA receptors antagonist and agonist of the NMDA polyamine receptor site) causes the maximal analgesic effect in the tail flick test in rats. The combined i.m. administration of dipyrone with IEM-1460 and spermine in threshold, noneffective alone doses according 1/5 part from their MED leads to decrease of MED dipyrone in the combination with IEM-1460 in 120 times, and MED dipyrone in combination with spermine--in 10 times. The combined i.m. administration of fentanyl with IEM-1460 and spermine in above mentioned threshold doses leads to decrease of MED fentanyl in the combination with IEM-1460 in 150 times, and MED fentanyl in the combination with spermine--in 15 times.

Two mechanisms of action of the adamantane derivative IEM-1460 at human AMPA-type glutamate receptors.[Pubmed:15834439]

Br J Pharmacol. 2005 Jul;145(5):656-63.

1. Antagonizing glutamatergic neurotransmission by blockade of AMPA-type glutamate receptors (GluR) is a promising pharmacological strategy for neuroprotection in neurodegenerative diseases and acute treatment of stroke. 2. We investigated the interaction of the adamantane derivative IEM-1460 with human wild-type and mutant AMPA-type GluR channels. Different recombinant homooligomeric human AMPA-type GluR channels and a rat nondesensitizing mutant GluR (GluR2 L504Y) channel were expressed in HEK293 cells and investigated using the patch-clamp technique in combination with ultrafast agonist application. 3. When IEM-1460 was coapplied with glutamate, an open channel block mechanism was observed at slow desensitizing GluR2 flip (>/=0.1 mM IEM-1460) and nondesensitizing GluR2 L504Y channels (>/=1 microM IEM-1460). 4. A competitive block of AMPA-type channels was observed with IC(50) values for the dose block curves of 0.1 mM IEM-1460 at human unmutated and 10 microM IEM-1460 at mutant GluR channels. 5. Nondesensitizing GluR2 L504Y channels were used to further characterize the block mechanism. After equilibration with the agonist, a current decay upon coapplication of glutamate and IEM-1460 was observed. The recovery from block was independent of the glutamate and IEM-1460 concentration. The extent of current inhibition as well as the time constant of current decay upon addition of the blocker to the test solution were dependent on agonist concentration; this strongly points to an additional competitive-like block mechanism of IEM-1460 at human AMPA-type GluR channels. 6. The data were interpreted in the frame of a molecular scheme with two binding sites of IEM-1460 at the receptor, one at the unliganded resting and the other at the fully liganded open state of the channels.

Peripheral and central routes of administration of quaternary ammonium compound IEM-1460 are equally potent in reducing the severity of nicotine-induced seizures in mice.[Pubmed:19145339]

Bull Exp Biol Med. 2008 Jul;146(1):18-21.

Peripheral administration of nicotinic receptor antagonists with a quaternary ammonium group (hexamethonium and chlorisondamine) did not prevent the development of seizures induced by systemic treatment with nicotine in the toxic dose. The Me3N+ group with stable positive charge inhibits transport of these compounds into the brain through the blood-brain barrier. Intracerebral and peripheral (intraperitoneal) administration of compound IEM-1460 with the Me3N+ group was equally potent in reducing the severity of nicotine-induced seizures in mice. This phenomenon is related to the fact that IEM-1460 acts as a nicotinic receptor antagonist and polyamine agonist, which increases blood-brain barrier permeability for polar compounds. These features contribute to IEM-1460 transport into the brain. High anticonvulsant activity of IEM-1460 on the model of nicotine-induced seizures is associated with combined blockade of nicotinic receptors (alpha3beta4 receptors) and glutamate receptors (GluR1 AMPA receptors).

Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.[Pubmed:22049415]

J Neurosci. 2011 Nov 2;31(44):15727-31.

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.

Characterization of AMPA receptor populations in rat brain cells by the use of subunit-specific open channel blocking drug, IEM-1460.[Pubmed:10536213]

Brain Res. 1999 Oct 30;846(1):52-8.

Dicationic adamantane derivative, IEM-1460, which selectively blocks GluR2-lacking, Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, was used to characterize the distribution of AMPA receptors among populations of rat brain cells. IEM-1460 inhibited kainate-induced inward currents (at -80 mV) in a dose-dependent manner. IEM-1460 concentrations producing 50% inhibition of kainate-induced current amplitude (IC50) varied greatly depending on the cell type studied. Striatal giant cholinergic interneurons and putative Bergmann glial cells isolated from the cerebellum were found to be highly sensitive to IEM-1460 block (IC50=2.6 microM), indicating the expression of GluR2-lacking AMPA receptor subtype. Among hippocampal and cortical non-pyramidal neurons, there were cell-to-cell differences in the pattern of AMPA receptor subtype expression. Some cells which are known to express AMPA receptors lacking GluR2 subunit exhibited high sensitivity of IEM-1460 block (IC50 about 1 microM) but in the others, the part of AMPA receptor population seemed to be represented by GluR2-having receptor subtype. The latter subtype was mainly expressed by pyramidal neurons isolated from hippocampus (IC50=1102 microM) and sensorimotor cortex (IC50=357 microM) which showed low affinity for IEM-1460 block. In conclusion, IEM-1460 can be utilized as an indicator of the distribution of AMPA receptor subtypes among populations of rat brain cells, and pharmacological detection of the absence of GluR2 subunit in AMPA receptor assembly can provide useful information for the interpretation of physiological events.