LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors

Neuropharmacology. 1998;37(1):1-12. doi: 10.1016/s0028-3908(97)00191-3.


The in vitro pharmacology of a structurally novel compound, LY341495, was investigated at human recombinant metabotropic glutamate (mGlu) receptor subtypes expressed in non-neuronal (RGT, rat glutamate transporter) cells. LY341495 was a nanomolar potent antagonist of 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD)-induced inhibition of forskolin-stimulated cAMP formation at mGlu2 and mGlu3 receptors (respective IC50S of 0.021 and 0.014 microM). At group I mGlu receptor expressing cells, LY341495 was micromolar potent in antagonizing quisqualate-induced phosphoinositide (PI) hydrolysis, with IC50 values of 7.8 and 8.2 microM for mGlu1a and mGlu5a receptors, respectively. Among the human group III mGlu receptors, the most potent inhibition of L-2-amino-4-phosphonobutyric acid (L-AP4) responses was seen for LY341495 at mGlu8, with an IC50 of 0.17 microM. LY341495 was less potent at mGlu7 (IC50 = 0.99 microM) and least potent at mGlu4 (IC50 = 22 microM). Binding studies in rat brain membranes also demonstrated nanomolar potent group II mGlu receptor affinity for LY341495, with no appreciable displacement of ionotropic glutamate receptor ligand binding. Thus, LY341495 has a unique range of selectivity across the mGlu receptor subtypes with a potency order of mGlu3 > or = mGlu2 > mGlu8 > mGlu7 >> mGlu1a = mGlu5a > mGlu4. In particular, LY341495 is the most potent antagonist yet reported at mGlu2, 3 and 8 receptors. Thus, it represents a novel pharmacological agent for elucidating the function of mGlu receptors in experimental systems.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acids / metabolism
  • Amino Acids / pharmacology*
  • Animals
  • Cell Line
  • Colforsin / pharmacology
  • Cyclic AMP / biosynthesis
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Humans
  • Prosencephalon / metabolism
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Xanthenes / metabolism
  • Xanthenes / pharmacology*


  • Amino Acids
  • Excitatory Amino Acid Antagonists
  • LY 341495
  • Receptors, Metabotropic Glutamate
  • Xanthenes
  • metabotropic glutamate receptor 2
  • Colforsin
  • Cyclic AMP