Discovery, synthesis, and structure-activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4493-500. doi: 10.1016/j.bmcl.2013.06.049. Epub 2013 Jun 25.

Abstract

A virtual screening approach using various in silico methodologies led to the discovery of 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one (1) as a moderately active negative allosteric modulator (NAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) showing high selectivity against the subtype mGluR1. Modifications of the parent compound by rational design yielded a series of highly potent derivatives which will serve as valuable starting points for further hit-to-lead optimization efforts toward a suitable drug candidate for the treatment of L-DOPA induced dyskinesia.

Keywords: Allosteric modulator; Metabotropic glutamate receptor; Virtual screening; l-DOPA induced dyskinesia; mGluR5.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Cells, Cultured
  • Drug Discovery*
  • Drug Evaluation, Preclinical*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Quinazolinones / chemistry*
  • Quinazolinones / pharmacology*
  • Rats
  • Receptor, Metabotropic Glutamate 5 / agonists*
  • Receptors, Metabotropic Glutamate / agonists
  • Structure-Activity Relationship
  • Toluidines / chemistry*
  • Toluidines / pharmacology*
  • User-Computer Interface*

Substances

  • 2-(m-tolylamino)-7,8-dihydroquinazolin-5(6H)-one
  • 4-aminoquinazoline
  • Quinazolines
  • Quinazolinones
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Toluidines
  • metabotropic glutamate receptor type 1