The voltage-dependent block of AMPA receptor (AMPAR) channels by a series of dicationic compounds was studied on native GluR2-lacking receptors of striatal giant interneurons isolated from rat brain slices. The dicationic derivatives of adamantane, dimethyladamantane, diphenyl, and phenylcyclohexyl were used. The voltage dependence of the blockade and of the unblocking rate constant suggests that the compounds permeate the open AMPAR channels. The permeation of adamantane derivatives was demonstrated previously. However, for derivatives of phenylcyclohexyl this finding is surprising because of the large dimensions of the phenylcyclohexyl moiety. All these compounds were found to get trapped in the closed state of the channel. However, time-dependent decrease of trapping was found. This effect is accelerated by hyperpolarization, suggesting that blockers can escape from trapping into the cytoplasm channel. Importantly, there is a correlation between permeation through the open channel and escape from the closed channel. Dicationic compounds were demonstrated to block open and closed AMPAR channels from inside of the cell Thus, trapping of AMPAR channel blockers after agonist removal does not prevent escape of blockers into the cytoplasm It is concluded that closure of the AMPAR channel gates at the extracellular vestibule is not coupled with plugging of the pathway between the selectivity filter and cytoplasm. Possible physiological importance of this blocking mechanism is discussed.
Neuropharmacology 54(4): 653-64 (2008)

Adamantane derivative IEM-1676 (Ad-N+H2-(CH2)5-N+Me3) causes open-channel block of Ca2+ permeable AMPA receptors when applied externally, but internal application results in both closed- and open-channel block. The relationships between blocking action of externally and internally applied IEM-1676 were studied using patch clamp technique. Extracellular action of IEM-1676 is decreased by its intracellular application, thus indicating overlap of the binding site at external and internal application. We demostrated that internal closed-channel block is voltage-dependent and occurs at the site where externally applied drug is trapped. We conclude that the selectivity filter of the closed AMPA receptor channel is not occluded and remains permeable for organic cations.
J Mol Neurosci. 39(1-2): 169-74 (2009)