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ACS Medicinal Chemistry Letters
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and mGlu3 NAMs in a mouse tail suspensions test, to assess
potential antidepressant phenotype, indicated the mGlu3 inhiꢀ
bition is the dominant mGlu subtype responsible for efficacy.
Further antiꢀdepressant paradigms in both mice and rats are
underway, and results will be reported in due course.
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AUTHOR INFORMATION
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Corresponding Authors
*(CWL). Phone: 1 615ꢀ322ꢀ8700. Fax: 1 615ꢀ936ꢀ4381. Email:
Author Contributions
CWL wrote the manuscript and oversaw the medicinal chemistry.
KAE designed compounds and JLE, KAB, MFL, MBM and SRB
performed chemical synthesis. PJC, ALR and CMN performed and
analyzed molecular pharmacology data. SC, RDMM, TMB and ALB
oversaw and analyzed in vitro and in vivo DMPK data. CKJ and MB
performed and analyzed the mouse tail suspension assay/data.
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of Mood Disorders; Proceedings of the 40th Annual Meeting of the
Society for Neuroscience, San Diego, CA, Nov 13−17, 2010; Soci
ety for Neuroscience: Washington, DC, 2010; 886.14/VV7.
All authors have given approval to the final version of the manuscript.
Acknowledgement
The authors would also like to thank William K. Warren, Jr. and
the William K. Warren Foundation who funded the William K.
Warren, Jr. Chair in Medicine (to C.W.L.), and the National
Institute of Mental Health for funding R01MH099269 (to
K.A.E.).
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Schneider, M.; Bessif, A.; RoyerꢀUrios, I.; Parron, D.; Legrand, C.;
Mahious, N.; Girard, F.; Le Poul, E. An mGluR2/3 negative alloꢀ
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mGlu2/3 antagonists for the treatment of autistic disorders. PCT Int.
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ASSOCIATED CONTENT
Supporting Information. General methods for the synthesis and
characterization of all compounds, and methods for the in vitro
and in vivo DMPK protocols and supplemental figures. This maꢀ
terial is available free of charge via the Internet at
ABBREVIATIONS
Metabotropic glutamate receptor (mGlu); PAM, positive allosteric moduꢀ
lator; NAM, negative allosteric modulator; mGlu3, metabotropic glutamate
receptor subtype 3; PBL, plasma:brain level; Kp, plasma:brain partitioning
coefficient; Kp,uu, unbound plasma:unbound brain partitioning coefficient;
DCM, dichloromethane; DABCO, 1,4ꢀdiazabicylco[2.2.2]octane; MED,
minimum effective dose; CYP; cytochrome P450; PK/PD, pharmacokinetꢀ
ic/pharmacodynamics; DMPK, drug metabolism and pharmacokinetics;
DtBAD, diꢀtertꢀbutyl azodicarboxylate.
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