ZK200775, ZK187638, ZK238519 and ZK166350: comparison of different potent antagonists of AMPA-type glutamate receptor channels and their potential role for neuroprotection

Neurodegeneration in several diseases like amyotrophic lateral sclerosis is at least in part caused by chronic excitotoxicity. AMPA-receptor-mediated fast excitatory synaptic transmission induces an increase of the intracellular calcium-concentration, that might explain one pathway in the pathophysiological model of chronical excitotoxicity. Therefore, neuroprotection by antagonising AMPA-receptor mediated synaptic transmission by selective AMPA-type-receptor blockers is a promising strategy albeit AMPA-type-receptor blockers show a lot of (neuro)toxic side effects. An urgent aim of drug design is to develop more selective AMPA-type- receptor blockers (e.g. subunit selectivity) that results in less side effects and better tolerability. Patch clamp experiments are a useful method to elucidate specific pharmacological effects on kinetics of AMPA-type receptor channels. experiments were performed on recombinant homomeric and heteromeric AMPA receptor channels expressed in HEK293-cells. Drug application was performed using a fast application system based on a piezo driven liquid filament switch. Our study shows four different AMPA-receptor antagonists (ZK200775, ZK187638, ZK238519, ZK166350), differentiated in their specific electrophysiological pharmacological properties and blocking mechanisms via different drug application and patch clamp techniques. We observed a dose-dependent competitive block effect for ZK200775 and ZK238519 and a non-competitive block effect for ZK187638 and ZK166350. The quantitative details of the interaction of the tested compounds with AMPA type receptor channels were integrated in reaction models that allow for computer simulation. The results are a quantitative basis for further drug design testing analogues of the compounds in vivo (motoneuron cultures and SOD1 animal model of ALS) and in vitro.