, Volume 179, Issue 1, pp 271–283 | Cite as

Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)

  • Michael P. JohnsonEmail author
  • David Barda
  • Thomas C. Britton
  • Renee Emkey
  • William J. Hornback
  • G. Erik Jagdmann
  • David L. McKinzie
  • Eric S. Nisenbaum
  • Joseph P. Tizzano
  • Darryle D. Schoepp
Original Investigation



To increase subtype selectivity and provide a novel means to alter receptor function, we discovered and characterization potentiators for the metabotropic glutamate 2 receptor (mGlu2).

Methods and results

A class of 3-pyridylmethylsulfonamides (e.g., 3-MPPTS; 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) were found to be potent, subtype-selective potentiators of human and rat mGlu2. The sulfonamides increased agonist potency in functional assays but did not displace orthosteric radiolabeled antagonist or agonist binding to cloned mGlu2 receptors. Rather, the modulators increased the affinity of most of the orthosteric agonists including glutamate, DCG-IV (2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)glycine), and LY354740 (1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate). In striatal brain slices, LY354740 inhibited evoked excitatory postsynaptic potentials (EPSPs) equally well following either a low- (0.06 Hz) or high (4 Hz)-frequency stimulation of corticostriatal afferents. In contrast, the mGlu2 potentiator cyPPTS (2,2,2-trifluoro-N-[3-(cyclopentyloxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) inhibited striatal EPSPs only at higher frequencies of stimulation (2 and 4 Hz). Several sulfonamides including 4-MPPTS, 4-APPES (N-[4-(4-carboxamidophenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride monohydrate) and/or CBiPES N-[4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride) were tested in mGlu2/3 agonist-sensitive rodent model(s) of anxiety and psychosis. As seen with LY354740, both 4-MPPTS and 4-APPES were efficacious in a rat fear-potentiated startle paradigm. Likewise in mice, CBiPES attenuated a stress-induced hyperthermia and PCP-induced hyperlocomotor activity. Furthermore, CBiPES mediated alteration in PCP-induced hyperlocomotor activity was sensitive to mGlu2/3 antagonist pretreatment.


Taken together, the data indicate mGlu2 receptor potentiators have a unique use-dependent effect on presynaptic glutamate release, and show efficacy in several mGlu2/3-sensitive animal models of psychiatric disorders.


Allosteric Modulator mGlu2 Receptor Spontaneous Locomotor Activity Positive Allosteric Modulator EPSP Amplitude 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors wish to thank the following individuals at Lilly Research Laboratories who contributed significantly to the scientific design and results: Sherri Andis, Mary Jo Chamberlain, Darrell S. Coleman, Kelly I. Griffey, John C. Hart, Steven S. Henry, Bryan G. Johnson, Gerard M. Kelly, Mark A. Muhlhauser, Grant M. Vaught, Zhao-Qing Wong, and Jin Zhai.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Michael P. Johnson
    • 1
    Email author
  • David Barda
    • 1
  • Thomas C. Britton
    • 1
  • Renee Emkey
    • 1
  • William J. Hornback
    • 1
  • G. Erik Jagdmann
    • 1
  • David L. McKinzie
    • 1
  • Eric S. Nisenbaum
    • 1
  • Joseph P. Tizzano
    • 1
  • Darryle D. Schoepp
    • 1
  1. 1.Lilly Research Laboratories, Eli Lilly and CompanyLilly Corporate CenterUSA

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