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. Epub 2017 Apr 27.

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.

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / genetics
  • Binding Sites / drug effects
  • Binding Sites / genetics
  • Calcium / metabolism
  • Dose-Response Relationship, Drug
  • Doxycycline / pharmacology
  • Electric Stimulation
  • Excitatory Amino Acid Agents / chemistry
  • Excitatory Amino Acid Agents / pharmacology
  • Glutamic Acid / pharmacology
  • Glycine / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Patch-Clamp Techniques
  • Protein Domains / drug effects
  • Protein Domains / genetics
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*
  • Transfection

Substances

  • Excitatory Amino Acid Agents
  • GNE-9278
  • Pyrimidinones
  • Receptors, N-Methyl-D-Aspartate
  • Sulfonamides
  • Glutamic Acid
  • Doxycycline
  • Calcium
  • Glycine