ACS Medicinal Chemistry Letters
Letter
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anxiolytic activity to the parent compounds but at significantly
lower doses. We have recently obtained screening data in 63
additional receptors and ion channels (NIDA-ATDP−DPMCDA-
Caliper Life Sciences contract) for 7i. At a concentration of
100 nM, there was no significant binding (<13% inhibition) at any
of these other targets, highlighting the selectivity of this compound
(Supporting Information, Table S1). Further evaluation of 7i in rat
models of cocaine self-administration, incubation of cocaine craving,
and reinstatement of cocaine-seeking behavior are presently under-
way.
ASSOCIATED CONTENT
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S
* Supporting Information
Experimental details for the synthesis and purification of the
compounds and the in vitro and in vivo pharmacological
characterizations of the compounds in this manuscript. This
material is available free of charge via the Internet at http://
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(15) Rocher, J. P.; Bonnet, B.; Bolea, C.; Lutjens, R.; Le Poul, E.;
Poli, S.; Epping-Jordan, M.; Bessis, A. S.; Ludwig, B.; Mutel, V.
mGluR5 negative allosteric modulators overview: a medicinal
chemistry approach towards a series of novel therapeutic agents.
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(16) Kulkarni, S. S.; Zou, M. F.; Cao, J.; Deschamps, J. R.; Rodriguez,
A. L.; Conn, P. J.; Newman, A. H. Structure-activity relationships
comparing N-(6-methylpyridin-yl)-substituted aryl amides to 2-
methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4-(substi-
tuted-arylethynyl)thiazoles as novel metabotropic glutamate receptor
subtype 5 antagonists. J. Med. Chem. 2009, 52, 3563−3575.
(17) Keck, T. M.; Rutledge, R. P.; Zhang, P.; Zou, M. F.; Newman, A.
H. Identifying Novel mGluR5 Negative Allosteric Modulators As Tools for
in Vivo Investigation in Addiction; Program No. 263.13/EE6; Society for
Neuroscience: Washington, DC, 2011.
AUTHOR INFORMATION
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Corresponding Author
*Tel: +1-443-740-2887. Fax: +1-443-740-2111. E-mail: anewman@
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
This research was funded by the NIDA Intramural Research
Program. T.M.K. was supported by an NIH Postdoctoral
Intramural Research Training Award (IRTA) Fellowship, and
R.P.R. was supported by an NIH Postbaccalaureate IRTA
Fellowship.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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mGluR5-transfected HEK 293A cells were generously provided
by Dr. Karen O'Malley of Washington University in St. Louis.
We acknowledge the NIDA-DPMCDA ATDP contract
N01DA-8-8877 for providing off-target screening data. Thanks
to Theresa Kopajtic for help in developing the radioligand
binding assay and members of Sergi Ferre's laboratory for help
with the ELISA assay. Thanks to Jonathan Katz and Gianluigi
Tanda for useful discussions regarding data and figure
presentation.
ABBREVIATIONS
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mGluR, metabotropic glutamate receptor; GPCR, G protein-
coupled receptor; NAM, negative allosteric modulator; MPEP,
2-methyl-6-(phenylethynyl)pyridine; MTEP, 3-((2-methyl-4-
thiazolyl)ethynyl)pyridine; SAR, structure−activity relation-
ships; IP3, D-myo-inositol 1,4,5 trisphosphate; IP1, D-myo-
inositol 1 phosphate; TBAF, tetrabutylammonium formate
(18) Keck, T. M.; Zhang, P.; Zou, M. F.; Newman, A. H. Novel
mGluR5 Negative Allosteric Modulators for in Vivo Investigation;
Program No. 272.5/LL5; Society for Neuroscience: San Diego, CA,
2010.
(19) Romano, C.; Sesma, M. A.; McDonald, C. T.; O'Malley, K.; Van
den Pol, A. N.; Olney, J. W. Distribution of metabotropic glutamate
receptor mGluR5 immunoreactivity in rat brain. J. Comp. Neurol. 1995,
355, 455−469.
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