Discovery of Orally Efficacious Tetracyclic Metabotropic Glutamate Receptor 1 (mGluR1) Antagonists for the Treatment of Chronic Pain

J Med Chem. 2007 Nov 15;50(23):5550-3. doi: 10.1021/jm070590c. Epub 2007 Oct 11.

Abstract

Metabotropic glutamate receptor 1 (mGluR1) plays important roles in the neurotransmission and pathogenesis of several neurological disorders, including chronic pain. Antagonists of mGlur1 are suggested to be useful for the treatment of pain. Herein, we report the discovery of a novel series of tetracyclic mGluR1 antagonists, such as 23c and 23e, with oral efficacy of ED50 of 8 and 5.1 mg/kg, respectively, in rat spinal nerve ligation neuropathic pain model.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Area Under Curve
  • Chronic Disease
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / chemistry
  • Indazoles / pharmacology
  • Morpholines / chemical synthesis
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Pain / drug therapy*
  • Peripheral Nervous System Diseases / drug therapy
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Heterocyclic Compounds, 4 or More Rings
  • Indazoles
  • Morpholines
  • Pyridines
  • Pyrroles
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1