BAY36-7620: A Potent Non-Competitive mGlu1 Receptor Antagonist with Inverse Agonist Activity.

  1. Fiona Y. Carroll1,
  2. Andreas Stolle2,
  3. Philip M. Beart3,
  4. Arnd Voerste2,
  5. Isabelle Brabet1,
  6. Frank Mauler2,
  7. Cécile Joly1,
  8. Horst Antonicek2,
  9. Joël Bockaert1,
  10. Thomas Müller2,
  11. Jean Philippe Pin1 and
  12. Laurent Prézeau1
  1. 1Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique de Pharmacologie-Endocrinologie–UPR 9023, Montpellier, France (F.Y.C., I.B., C.J., J.B., J.P.P., L.P.); 2Bayer AG, PharmaResearch, Wuppertal, Germany (A.S., A.V., F.M., H.A., T.M.); and 3Department of Pharmacology, Monash University, Victoria, Australia (P.M.B.)

    Abstract

    l-Glutamate (Glu) activates at least eight different G protein-coupled receptors known as metabotropic glutamate (mGlu) receptors, which mostly act as regulators of synaptic transmission. These receptors consist of two domains: an extracellular domain in which agonists bind and a transmembrane heptahelix region involved in G protein activation. Although new mGlu receptor agonists and antagonists have been described, few are selective for a single mGlu subtype. Here, we have examined the effects of a novel compound, BAY36-7620 [(3aS,6aS)- 6a-Naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on], on mGlu receptors (mGlu1–8), transiently expressed in human embryonic kidney 293 cells. BAY36-7620 is a potent (IC50 = 0.16 μM) and selective antagonist at mGlu1 receptors and inhibits >60% of mGlu1a receptor constitutive activity (IC50 = 0.38 μM). BAY36-7620 is therefore the first described mGlu1 receptor inverse agonist. To address the mechanism of action of BAY36-7620, Glu dose-response curves were performed in the presence of increasing concentrations of BAY36-7620. The results show that BAY36-7620 largely decreases the maximal effect of Glu. Moreover, BAY36-7620 did not displace the [3H]quisqualate binding from the Glu-binding pocket, further indicating that BAY36-7620 is a noncompetitive mGlu1 antagonist. Studies of chimeric receptors containing regions of mGlu1 and regions of DmGluA, mGlu2, or mGlu5, revealed that the transmembrane region of mGlu1 is necessary for activity of BAY36-7620. Transmembrane helices 4 to 7 are shown to play a critical role in the selectivity of BAY36-7620. This specific site of action of BAY36-7620 differs from that of competitive antagonists and indicates that the transmembrane region plays a pivotal role in the agonist-independent activity of this receptor. BAY36-7620 will be useful to further delineate the functional importance of the mGlu1 receptor, including its putative agonist-independent activity.

    Footnotes

    • Send reprint requests to: Dr. Laurent Prézeau, Center INSERM-CNRS de Pharmacologie-Endocrinologie - UPR 9023, Laboratoire des Mécanismes Moléculaires des Communications Cellulaires, 141 rue de la Cardonille 34094 Montpellier cedex 5 – France. E-mail:prezeau{at}montp.inserm.fr

    • This work was supported by Grants from the Centre National de la Recherche Scientifique (CNRS; J.B.), Bayer company (France and Germany) (J.B.), the Fondation pour la Recherche Médicale (J.B.), the “Action Incitative Physique et Chimie du Vivant” (PCV00–134) from the CNRS (J.P.P.), the program “Molécules et Cibles Thérapeutiques” from Institut National de la Santé et de la Recherche Médicale (INSERM) and CNRS (J.P.P.), the association Retina France (J.P.P.), by the Australian National Health and Medical Research Council (NH&MRC) Grant (960001) (P. M.B.). F.C. was supported by an INSERM/NH&MRC exchange fellowship (997012).

    • Abbreviations:
      mGlu
      metabotropic glutamate
      GPCR
      G protein-coupled receptor
      CaSR
      calcium-sensing receptor
      ECD
      extracellular domain
      MPEP
      2-methyl-6-(phenylethynyl)pyridine
      TM
      transmembrane
      CPCCOEt
      7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester
      MCPG
      S-α-methyl-4-carboxyphenylglycine
      HEK
      human embryonic kidney
      PLC
      phospholipase C
      IP
      inositol phosphate
      Glu
      l-glutamate
      QA
      quisqualate
      • Received December 27, 2000.
      • Accepted February 12, 2001.
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    1. Molecular Pharmacology May 1, 2001 vol. 59 no. 5 965-973
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