title: MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit.
abstract: GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders.
authors.affiliation: Mnemosyne Pharmaceuticals, Inc. (now Luc Therapeutics) 400 Technology Square, Cambridge, MA 02139, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Volkmann
authors.affiliation: Mnemosyne Pharmaceuticals, Inc. (formerly Luc Therapeutics) 400 Technology Square, Cambridge, MA 02139, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Fanger
authors.affiliation: Mnemosyne Pharmaceuticals, Inc. (formerly Luc Therapeutics) 400 Technology Square, Cambridge, MA 02139, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Anderson
authors.affiliation: Jubilant Biosys Limited, #96, Industrial Suburb 2nd Stage, Yeshwantpur Bangalore - 560 022 Karnataka, India.
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Sirivolu
authors.affiliation: Jubilant Discovery Services, Inc. 365 Phoenixville Pike, Malvern, PA 19355, United States of America.
authors.forename: Kathy
authors.initials: K
authors.lastname: Paschetto
authors.affiliation: Jubilant Discovery Services, Inc. 365 Phoenixville Pike, Malvern, PA 19355, United States of America.
authors.forename: Earl
authors.initials: E
authors.lastname: Gordon
authors.affiliation: Aptuit Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Virginio
authors.affiliation: Neuroservice, Domaine de Saint Hilaire, 595 rue Pierre Berthier, CS 30531-13593 Aix en Provence cedex 03, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gleyzes
authors.affiliation: Neuroservice, Domaine de Saint Hilaire, 595 rue Pierre Berthier, CS 30531-13593 Aix en Provence cedex 03, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Buisson
authors.affiliation: Neuroservice, Domaine de Saint Hilaire, 595 rue Pierre Berthier, CS 30531-13593 Aix en Provence cedex 03, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Steidl
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, United States of America.
authors.forename: Susanna B
authors.initials: SB
authors.lastname: Mierau
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, United States of America.
authors.forename: Michela
authors.initials: M
authors.lastname: Fagiolini
authors.affiliation: Mnemosyne Pharmaceuticals, Inc. (formerly Luc Therapeutics) 400 Technology Square, Cambridge, MA 02139, United States of America.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014981:Xenopus; D006834:Hydrazines; D000096926:Benzenesulfonamides
chemical_list: D002118:Calcium; D018698:Glutamic Acid; D005998:Glycine; D021122:Protein Subunits; D011719:Pyrazines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C000609092:MPX-004; C000609093:MPX-007; C464436:NR2D NMDA receptor; C574512:TCN 201; D006834:Hydrazines; D000096926:Benzenesulfonamides
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