ACS Medicinal Chemistry Letters
Letter
signaling profiles of positive allosteric modulators of mGlu5 determine
differences in in vivo activity’. Biol. Psychiatry 2013, 73, 501−509.
(12) Conn, P. J.; Lindsley, C. W.; Meiler, J.; Niswender, C. M.
Opportunities and challenges in the discovery of allosteric modulators
of GPCRs for the treatment of CNS disorders. Nat. Rev. Drug
Discovery 2014, 13, 692−708.
ACKNOWLEDGMENTS
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The authors would also like to thank Dr. Brian Hrupka, Heidi
Huysmans, Christ Nolten, Gerd Van Den Kieboom, and Sofie
Versweyveld for their contribution with animal surgery and data
collection.
(13) MacDonald, G. J.; Lindsley, C. W. A unique industrial-academic
collaboration towards the next generation of schizophrenia therapeu-
tics’. Curr. Top. Med. Chem. 2014, 14, 304−312.
(14) Zhou, Y.; Manka, J.; Rodriguez, A. L.; Weaver, C. D.; Jones, C.
K.; Conn, P. J.; Lindsley, C. W.; Stauffer, S. R. N-Aryl piperazines as
selective mGlu5 potentiators with improved physiochemical properties
and efficacy in a rodent model predictive of antipsychotic activity’. ACS
Med. Chem. Lett. 2010, 1, 433−438.
(15) Williams, R.; Manka, J. T.; Rodriguez, A. L.; Vinson, P. N.;
Niswender, C. M.; Weaver, C. D.; Jones, C. K.; Conn, P. J.; Lindsley,
C. W.; Stauffer, S. R. Synthesis and SAR of centrally active mGlu5
positive allosteric modulators based on an aryl acetylenic bicyclic
lactam scaffold. Bioorg. Med. Chem. Lett. 2011, 21, 1350−1353.
(16) Manka, J.; Zhou, Y.; Williams, R.; Weaver, C. D.; Dawson, E. S.;
Steckler, T.; Lavreysen, H.; Mackie, C.; Bartolome, J. M.; Macdonald,
G. J.; Conn, P. J.; Lindsley, C. W.; Stauffer, S. R. Optimization of an
ether series of mGlu5 positive allosteric modulators: molecular
determinants of MPEP-site interaction cross-over. Bioorg. Med.
Chem. Lett. 2012, 22, 6481−6485.
(17) Noetzel, M. J.; Gregory, K. J.; Vinson, J. T.; Manka, S. R.;
Stauffer, S. R.; Daniels, S. J.; Lindsley, C. W.; Niswender, C. M.; Xiang,
Z.; Conn, P. J. A novel metabotropic glutamate receptor 5 PAM acts at
a unique site and confers stimulus bias to mGlu5 signaling. Mol.
Pharmacol. 2013, 83, 835−847.
(18) Bartolome-Nebreda, J. M.; Conde-Ceide, S.; Delgado, F.; Pas
tor, J.; Pena, M. A.; Trabanco, A. A.; Tresadern, G.; Wassvik, C. M.;
Stauffer, S. R.; Jadhav, S.; Days, E.; Weaver, C. D.; Lindsley, C. W.;
Niswender, C. M.; Jones, C. K.; Conn, P. J.; Rombouts, F.; Lavreysen,
H.; Macdonald, G. J.; Mackie, C.; Steckler, T. Dihydrothiazolopyr-
idone derivatives as a novel family of positive allosteric modulators of
the mGlu5 receptor. J. Med. Chem. 2013, 56, 7243−7259.
(19) Turlington, M.; Malosh, C.; Jacobs, J.; Manka, J. T.; Vinson, P.
N.; Gogi, K.; Jadhav, S.; Herman, E. J.; Lavreysen, H.; Mackie, C.;
Bartolome, J. M.; Macdonald, G. J.; Steckler, T.; Daniels, J. S.; Weaver,
C. D.; Niswender, C. M.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.;
Stauffer, S. R. Tetrahydronaphthyridine and dihydronapthyridinone
ethers as positive allosteric modulators of the metabotropic glutamate
receptor 5 (mGlu5). J. Med. Chem. 2014, 57, 5620−5637.
ABBREVIATIONS
■
DCM, dichloromethane; AHL, amphetamine-induced hyper-
locomotion; CFC, contextual fear conditioning; MED,
minimum effective dose; LTD, long-term depression; metab-
otropic glutamate receptor, (mGlu); FJC, fluorjade; PAM,
positive allosteric modulator
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