NMDA Receptor Modulators

 

NMDA receptors mediate the slow component of excitatory synaptic transmission and require the binding of both glutamate and glycine for channel activation.  Glycine binds to the GluN1 subunits, which have eight splice variants encoded by a single gene.  The GluN2 subunits (GluN2A-D) bind glutamate, and are encoded by four distinct genes.  The GluN2 subunits control many of the functional and pharmacological properties of the receptor, including agonist EC50, single channel open time and open probability, as well as deactivation-time course following removal of glutamate.  NMDA receptor deactivation-time course determines the time course for the slow, Ca2+-permeable component of synaptic transmission.  Typically, NMDA receptors are blocked by extracellular Mg2+ at resting membrane potentials, and the requirements of the glutamate release and depolarization-induced relief of Mg2+ block have led to the idea that the NMDA receptors act as coincidence detectors in the brain.   The Mg2+ IC50 and the kinetics of block and unblock also vary according to the GluN2 subunit.

In collaboration with Dr. Steve Traynelis of the Emory Pharmacology Department, the lab has conducted high-throughput screens and bioinformatics studies to identify a number of GluN2 subunit-selective modulators as leads in initial SAR studies and often, subsequent animal models of behavior.

In addition, the Liotta Research Group has completed extensive SAR studies on two classes of subunit selective potentiators.  One series, a class of pyrrolidinone analogs, represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.  The compounds of the second class of potentiators, the title compound of which is referred to as CIQ, were the first allosteric modulators of the GluN2C and GluN2D subunits to be discovered with strong subunit-selectivity.2,3  We are currently studying CIQ in preclinical animal models of fear, learning, and schizophrenia, and we are continually studying the SAR around this compound to further advance the drug-like properties of the series.

The lab has also identified and developed two distinct classes of GluN2C and GluN2D subunit selective antagonists, including a quinazolin-4-one scaffold4 and a pyrazoline-containing scaffold.5,6  These GluN2C and GluN2D inhibitors are being further studied in terms of the SAR and are being taken forward as agents for the treatment of Parkinson’s disease.

 

 Figure prepared by Strong, K.L.; Jing, Y.; Prosser, A.R.; NMDA receptor modulators: an updated patent review (2013-2014). Expert Opinion on Therapeutic Patents. Manuscript accepted.