Common Binding Site for Externally and Internally Applied AMPA Receptor Channel Blockers

Abstract

Adamantane derivative IEM-1676 (Ad-N(+)H(2)-(CH(2))(5)-N(+)Me(3)) causes open-channel block of Ca(2+)-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 was decreased by its intracellular application, thus suggesting that the binding sites of the externally and internally applied drug coincide or at least overlap significantly. We demonstrated that internal closed-channel block is voltage-dependent and occurs at the region where the 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.

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…When applied intracellularly, 229 was able to block Ca 2+ permeable AMPARs (that do not incorporate the GluR2 subunit) both with and without the agonist present, that is, it acted as an open channel blocker and a closed channel blocker. The extracellular blocking of 229 could be decreased by intracellular 229 , showing that the binding site in both cases is the same or at least overlapping significantly . While a clinical use of the AMPAR channel blockers reported here has not been disclosed, they found several applications in preclinical research.…”

“…The extracellular blocking of 229 could be decreased by intracellular 229, showing that the binding site in both cases is the same or at least overlapping significantly. 480 While a clinical use of the AMPAR channel blockers reported here has not been disclosed, they found several applications in preclinical research. Populations of AMPARs in various rat brain cell populations have been characterized using 225, 481 finding that 225 is a convenient marker for the absence of the GluR2 subunit in AMPARs.…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Some compounds (e.g., phenylcyclohexyl derivative IEM-1925) can permeate the channel, allowing closed channels to escape from block (Tikhonova et al, 2008). Other blockers [e.g., adamantane derivative IEM-1676 (Tikhonova et al, 2008)] produce a voltage-dependent closed channel block from the intracellular compartment in addition to open channel block from the extracellular compartment (Tikhonova et al, 2009). Association of AMPA receptors with TARPs ␥2, ␥3, and ␥8 reduces channel block by N 1 -naphthylacetylspermine ), an intriguing finding because TARPs also increase channel opening frequency (Tomita et al, 2005a) (see section II.H).…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…There are variations on the blocking mechanism, exemplified by the phenylcyclohexyl derivative IEM-1925, which permeates and exits the channel on the intracellular side, allowing closed channels to escape from block (Tikhonova et al, 2008). The adamantane derivative IEM-1676 produces a voltage-dependent closed channel block from the intracellular compartment, in addition to open channel block from the extracellular compartment (Tikhonova et al, 2009). Some auxiliary subunits associated with the AMPA receptor reduce the inhibition of channel blockers (Kott et al, 2009;Jackson et al, 2011;Poulsen et al, 2014b;Soto et al, 2014) (Section III.…”