Acyl-2-aminobenzimidazoles: a novel class of neuroprotective agents targeting mGluR5

Bioorg Med Chem. 2015 May 1;23(9):2211-20. doi: 10.1016/j.bmc.2015.02.054. Epub 2015 Mar 6.

Abstract

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for treating traumatic brain injury (TBI). Using computational and medicinal methods, the structure-activity relationship of a class of acyl-2-aminobenzimidazoles (1-26) is reported. The new compounds are designed based on the chemical structure of 3,3'-difluorobenzaldazine (DFB), a known mGluR5 PAM. Ligand design and prediction of binding affinities of the new compounds have been performed using the site identification by ligand competitive saturation (SILCS) method. Binding affinities of the compounds to the transmembrane domain of mGluR5 have been evaluated using nitric oxide (NO) production assay, while the safety of the compounds is tested. One new compound found in this study, compound 22, showed promising activity with an IC₅₀ value of 6.4 μM, which is ∼20 fold more potent than that of DFB. Compound 22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions.

Keywords: Computer-aided drug design; Metabotropic glutamate receptor; Neuroprotection; Positive allosteric modulator; Traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Computer-Aided Design
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / chemical synthesis
  • Excitatory Amino Acid Antagonists / chemistry
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / classification*
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Structure-Activity Relationship

Substances

  • Benzimidazoles
  • Excitatory Amino Acid Antagonists
  • Neuroprotective Agents
  • Receptor, Metabotropic Glutamate 5
  • Nitric Oxide