A virtual screening hit reveals new possibilities for developing group III metabotropic glutamate receptor agonists

J Med Chem. 2010 Apr 8;53(7):2797-813. doi: 10.1021/jm901523t.


(R)-PCEP (3-amino-3-carboxypropyl-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC(50) of 1.0 +/- 0.2 microM at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC(50) of 43 +/- 16 microM and is thus significantly more potent than L-AP4 (EC(50) of 249 +/- 106 microM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Evaluation, Preclinical / methods*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Phosphinic Acids / chemical synthesis
  • Phosphinic Acids / chemistry
  • Phosphinic Acids / metabolism
  • Phosphinic Acids / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • User-Computer Interface*


  • Phosphinic Acids
  • Receptors, Metabotropic Glutamate