2. Academic Validation
  3. A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain

A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain

  • Neuropharmacology. 2017 Jul 15;121:204-218. doi: 10.1016/j.neuropharm.2017.04.041.
Tzu-Ming Wang 1,  Brandon M Brown 1,  Lunbin Deng 1,  Benjamin D Sellers 2,  Patrick J Lupardus 3,  Heidi J A Wallweber 3,  Amy Gustafson 4,  Evera Wong 1,  Matthew Volgraf 2,  Jacob B Schwarz 2,  David H Hackos 5,  Jesse E Hanson 6
Affiliations

Affiliations

  • 1 Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 2 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3 Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 4 Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 5 Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 6 Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
PMID: 28457974 DOI: 10.1016/j.neuropharm.2017.04.041
Abstract

Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs. Modulation by GNE-9278 is state-dependent and significantly alters extracellular domain pharmacology. The unique properties and structural determinants of GNE-9278 reveal new modulatory potential of the iGluR TMD.

Keywords

118009479); 20938953); 22432385); 3689); 4231127); CIQ (PubChem CID; GNE-3419 (PubChem CID; GNE-8016 (PubChem CID; GNE-9278 (PubChem CID; Ifenprodil (PubChem CID; NMDA receptor; Positive allosteric modulator; Transmembrane domain.

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