Glutamate is the primary excitatory neurotransmitter in the mammalian brain. AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid) is the subtype of glutamate receptors and also is a ligand-gated ion channel. It expresses primarily on postsynaptic membranes of excitatory synapses in the central nervous system. As we all know, AMPARs (AMPA receptors) can mediate the majority of fast synaptic transmission within the central nervous system (CNS). Thus, It is an attractive strategy for therapeutic intervention to inhibit or negatively modulate AMPARs in CNS disorders, such as epilepsy.

Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function, and localization. TARP-γ8, an accessory protein, also known as CACNG8, is transmembrane AMPAR regulatory protein-γ8. Generally, It and AMPAR can form the AMPAR-TARPγ8 receptor complex which can interact in cell membranes. Then, we will introduce a small molecule — JNJ-56022486. It can bind to a unique interface of the AMPAR-TARPγ8 complex. That probably alters the conformation of the receptor complex, to allow brain region-specific targeting of AMPARs.

JNJ-56022486 is an Orally Active Negative AMPA Receptor Modulator for Epilepsy Research

JNJ-56022486 is a negative AMPA receptor modulator with a K_i value of 19 nM. First, JNJ-55511118 has excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration.  Meanwhile, in rodent in vivo models, JNJ-55511118 shows a strong reduction in certain bands in EEG, transient hyperlocomotion, no motor impairment on the rotarod, and mild impairment in learning and memory. Furthermore, JNJ-55511118 shows strong, dose-dependent inhibition of neurotransmission within the hippocampus and a strong anti-convulsant effect.

In sum, JNJ-56022486 is an orally active negative AMPA receptor modulator and has selective for TARP-γ8.

Reference:

[1] Maher MP, Wu N, et al. J Pharmacol Exp Ther. 2016;357(2):394-414.

[2] Rosenbaum MI, Clemmensen LS, et al. Nat Rev Drug Discov. 2020;19(12):884-901.