title: Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s).
abstract: BACKGROUND
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, IN 46285, USA. johnson_michael_p@lilly.com
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Barda
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Britton
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.forename: William J
authors.initials: WJ
authors.lastname: Hornback
authors.forename: G Erik
authors.initials: GE
authors.lastname: Jagdmann
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Tizzano
authors.forename: Darryle D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D003521:Cyclopropanes / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D003521:Cyclopropanes; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D010622:Phencyclidine; D005998:Glycine
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