South San Francisco, Calif. – Genentech’s recent publication “Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design”, details the discovery of a new NMDA receptor PAM with potential implications for neurological disorders such schizophrenia. The drug was developed with the help of unique capabilities provided by the IonFlux HT automated patch clamp (APC) system.
N-methyl-D-asparate receptors (NMDAR) are ubiquitous proteins in the central nervous system thought to be involved in higher cognitive functions and memory formation. Antagonists for NMDAR have been approved for treatment of Alzheimer’s disease, while the receptor’s hypo-function has been associated with schizophrenia. PAMs are molecules capable of enhancing the receptor’s response to its naturally occurring modulator, increasing the receptor’s activity. Genentech published the discovery of a new PAM that is selective to a specific subtype (GluN2A) of the NMDAR subunits. Drug compound GNE-0723 is blood/brain barrier permeable and is ready for in vivo testing.
IonFlux HT was used to evaluate hits from a calcium influx screen and compare the effects of a series of GluN2A-selective PAMs. Due to the toxicity of the receptor to its host cells, incubation with an ion channel blocker is required to preserve cell health. This requires rapid changes of solutions across all patch clamp recording sites, a unique feature of the IonFlux system among other automated electrophysiology platforms. The authors explain how the IonFlux system was able to measure not only receptor activation, but also deactivation kinetics. The results were validated by manual patch clamp with a fast perfusion system: “Notably, the deactivation trends observed for each aromatic group in the automated platform matched the trends in the fast perfusion system.“
“IonFlux is the only APC with the sophisticated flow control necessary to run this assay. Continuous flow coupled with rapid compound switching sets the system apart from other technologies and provides the foundation for performing challenging ligand-gated drug screens such as NMDAR“, explained Dr. Cristian Ionescu-Zanetti, CTO at Fluxion Biosciences.
About Fluxion Biosciences
Fluxion Biosciences manufactures the IonFlux™ automated patch clamp system for ion channel drug discovery. The system deploys a unique in-plate cell attachment, recording and drug delivery system that provides rapid parallel recordings for ligand- and voltage-gated channels and facilitates complicated drug screening assays. Premier institutions globally use Fluxion’s pioneering platforms, including the IsoFlux liquid biopsy system and the BioFlux cell analysis system in various disease research areas, including cancer, microbiology, and immunology.