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.

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.

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 μM IEM‐1460).

A competitive block of AMPA‐type channels was observed with IC₅₀ values for the dose block curves of 0.1 mM IEM‐1460 at human unmutated and 10 μM IEM‐1460 at mutant GluR channels.

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.

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.