AMPA receptors are ionic transmembrane receptors of glutamate, which mediate rapid synaptic transmission in the central nervous system (CNS). Specifically, AMPAR exists in many parts of the brain and is the most common receptor in the nervous system. Meanwhile, phosphorylation of AMPAR can regulate channel localization, conductance, and opening probability. Nonetheless, AMPAR turns on and off rapidly, so it is responsible for most of the rapid excitatory synaptic transmission in the CNS. The permeability of AMPAR to calcium and other cations (such as sodium and potassium) is determined by the GluA2 subunit. Besides, this means that the main ions controlled by AMPAR are sodium and potassium, which distinguish AMPAR from NMDA receptors (other major ionic glutamate receptors in the brain).
Moreover, the subunit composition of AMPAR is also important for the regulation of this receptor. If AMPAR lacks a GluA2 subunit, it can be easily blocked by polyamines in a voltage-dependent manner. Furthermore, AMPAR is both a glutamate receptor and a cation channel. It is essential for plasticity and synaptic transmission in many postsynaptic membranes. Today, we will introduce a potent and selective AMPA receptor antagonist, YM90K.
YM90K is a Selective AMPA Receptor Antagonist with Neuroprotective Actions.
First of all, YM90K is a potent and selective AMPA receptor antagonist with a Ki of 84 nM. Importantly, YM90K is less potent in inhibiting kainate (Ki of 2.2 μM) and NMDA (Ki of 37 μM) receptors. YM90K has neuroprotective actions.
In the second place, YM90K (30 nmol) co-injected with AMPA or kainate into the rat striatum protects cholinergic neurons against AMPA- or kainate-induced neurotoxicity. Particularly, YM90K shows potent suppressive activity against audiogenic seizure in DBA/2 mice. ED50 values of YM90K against tonic seizure is 2.54 mg/kg by i.p.. Obviously, the duration of the anticonvulsant effects of YM90K is 30 min. In a global ischemia model, YM90K with 15 mg/kg by i.p. significantly prevents the delayed neuronal death in the hippocampal CA1 region in Mongolian gerbils when administered 1 h after 5-min ischemia. Additionally, The therapeutic time window for the neuroprotective effect of YM90K (30 mg/kg; i.p.) is 6 h. In a focal ischemia model, YM90K reduces the volume of ischemic damage in the cerebral cortex in F344 rats.
All in all, YM90K is a selective AMPA receptor antagonist with neuroprotective actions.
M Shimizu-Sasamata, et al. J Pharmacol Exp Ther. 1996 Jan;276(1):84-92.