NPS 2390

Metabotropic glutamate receptors (mGluRs), mediate excitatory synaptic transmission in the central nervous system. Potent and selective antagonists of the type I mGluRs (mGluR1 and mGluR5) are of interest as novel therapeutics for the treatment of various CNS disorders, such as pain, epilepsy, and stroke.^1,2 NPS 2390 is a first generation quinoxaline derivative that acts as a noncompetitive antagonist of mGluR1 and mGluR5 with IC₅₀ values equal to 5.2 and 82 nM, respectively).³ At concentrations up to 30 μM, NPS 2390 does not affect mGluR2 or mGluR8 or a standard collection of 37 additional receptors, ion channels, and enzymes.³ At a dose of 10 mg/kg, NPS 2390 displaced the specifically bound mGlu1R-selective antagonist, [³H]R214127, in rat cerebellum.⁴

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1. Ferraguti, F., Crepaldi, L., and Nicoletti, F. Metabotropic glutamate 1 receptor: Current concepts and perspectives. Pharmacol. Rev. 60(4), 536-581 (2008).

2. Mabire, D., Coupa, S., Adelinet, C., et al. Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists. J. Med. Chem. 48(6), 2134-2153 (2005).

3. VanWagenen, B.C., Smith, D.L., Artman, L.D., et al. Structure-activity relationship studies of NPS 2390: A potent and selective group I metabotropic glutamate receptor antagonist. Soc. Neurosci. 1-2 (2000).

4. Lavreysen, H., Janssen, C., Bischoff, F., et al. [³H]R214127: A novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists. Mol. Pharmacol. 63(5), 1082-1093 (2003).