Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators

  • Nat Struct Mol Biol. 2017 Feb;24(2):108-113. doi: 10.1038/nsmb.3329.
Xin Huang  1 ,  Paul L Shaffer  1 ,  Shawn Ayube  1 ,  Howard Bregman  2 ,  Hao Chen  3 ,  Sonya G Lehto  4 ,  Jason A Luther  5 ,  David J Matson  5 ,  Stefan I McDonough  5 ,  Klaus Michelsen  6 ,  Matthew H Plant  6 ,  Stephen Schneider  5 ,  Jeffrey R Simard  5 ,  Yohannes Teffera  7 ,  Shuyan Yi  2 ,  Maosheng Zhang  4 ,  Erin F DiMauro  2 ,  Jacinthe Gingras  5
Affiliations
  • 1. Department of Molecular Structure and Characterization, Amgen Inc., Cambridge, Massachusetts, USA.
  • 2. Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, USA.
  • 3. Department of Protein Technologies, Amgen Inc., Cambridge, Massachusetts, USA.
  • 4. Department of Neuroscience, Amgen Inc., Thousand Oaks, California, USA.
  • 5. Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.
  • 6. Department of Discovery Attribute Sciences, Amgen Inc., Cambridge, Massachusetts, USA.
  • 7. Department of Pharmacokinetics &Drug Metabolism, Amgen Inc., Cambridge, Massachusetts, USA.
PMID: 27991902 DOI: 10.1038/nsmb.3329
Abstract

Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.

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