ACS Medicinal Chemistry Letters
Letter
by molecular docking screening against a homology model.
MedChemComm 2015, 6, 2216.
for schizophrenia and drug addiction and have been selected as
candidates for GLP toxicity studies.
(9) Millan, M. J.; Dekeyne, A.; Newman-Tancredi, A.; Cussac, D.;
Audinot, V.; Milligan, G.; Duqueyroix, D.; Girardon, S.; Mullot, J.;
Boutin, J. A.; et al. S18616, a highly potent, spiroimidazoline agonist at
alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and
hypothermic actions in comparison with dexmedetomidine and
clonidine. J. Pharmacol. Exp Ther. 2000, 295 (3), 1192−1205.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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(11) Cerep, Le bois l’Eveq
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ue, 86600 Celle l’Evescault, France (www.
Experimental details for the synthesis of compounds 2−
(12) Revel, F. G.; Moreau, J.-L.; Gainetdinov, R. R.; Bradaia, A.;
Sotnikova, T. D.; Mory, R.; Durkin, S.; Groebke Zbinden, K.;
Norcross, R. D.; Meyer, C. A.; Metzler, V.; Chaboz, S.; Ozmen, L.;
Trube, G.; Pouzet, B.; Bettler, B.; Caron, M. G.; Wettstein, J. G.;
Hoener, M. C. TAAR1 activation modulates monoaminergic neuro-
transmission, preventing hyperdopaminergic and hypoglutamatergic
activity. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 8485−8490.
(13) Leo, D.; Mus, L.; Espinoza, S.; Sotnikova, T. D.; Hoener, M. C.;
Gainetdinov, R. R. Taar1-mediated modulation of presynaptic
dopaminergic neurotransmission: role of D2 dopamine autoreceptors.
Neuropharmacology 2014, 81, 81283−81291.
AUTHOR INFORMATION
Corresponding Author
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
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The authors declare no competing financial interest.
(14) Zhang, C.; Kenny, H. L.; Deese, A.; Ford, K. A.; Lightning, L.
K.; Fan, P. W.; Driscoll, J. P.; Halladay, J. S.; Hop, C. E.; Khojasteh, S.
C. Novel Mechanism for Dehalogenation and Glutathione Con-
jugation of Dihalogenated Anilines in Human Liver Microsomes:
Evidence for ipso Glutathione Addition. Chem. Res. Toxicol. 2011, 24,
1668−1677.
ACKNOWLEDGMENTS
The authors are grateful to Veit Metzler, Daniel
Chaboz, Roland Mory, and Daniel Zimmerli for their excellent
technical assistance. We would also like to thank Jean-Luc
Moreau, Stephan Kirchner, Thomas Hartung, and Giorgio
Cirelli for coordinating in vivo and safety studies, isotope
labeling, and formulation work.
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e Buchy, Sylvie
(15) Nelson, S. Molecular mechanisms of adverse drug reactions.
Curr. Ther. Res. 2001, 62, 885−899.
(16) Revel, F. G.; Moreau, J. L.; Pouzet, B.; Mory, R.; Bradaia, A.;
Buchy, D.; Metzler, V.; Chaboz, S.; Groebke Zbinden, K.; Galley, G.;
Norcross, R. D.; Tuerck, D.; Bruns, A.; Morairty, S. R.; Kilduff, T. S.;
Wallace, T. L.; Risterucci, C.; Wettstein, J. G.; Hoener, M. C. A new
perspective for schizophrenia: TAAR1 agonists reveal antipsychotic-
and antidepressant-like activity, improve cognition and control body
weight. Mol. Psychiatry 2013, 18, 543−556.
(17) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. Pseudoephedrine as a Practical Chiral Auxiliary for the
Synthesis of Highly Enantiomerically Enriched Carboxylic Acids,
Alcohols, Aldehydes, and Ketones. J. Am. Chem. Soc. 1997, 119, 6496−
6511.
ABBREVIATIONS
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TA, trace amine; TAAR1, trace amine associated receptor 1; h,
human; r, rat; SAR, structure−activity relationship; SOSA,
selective optimization of side activities; MCASE, Multiple
Computer Automated Structural Evaluation; GSH, glutathion;
CvB, covalent binding; HLM, human liver microsomes; Hhep,
human hepatocytes; CL, clearance
REFERENCES
■
(18) Schollkopf, U. Asymmetric Syntheses of Amino Acids via
̈
(1) Lindemann, L.; Hoener, M. C. A renaissance in trace amines
inspired by a novel GPCR family. Trends Pharmacol. Sci. 2005, 26,
274−281.
(2) Lam, V. M.; Espinoza, S.; Gerasimov, A. S.; Gainetdinov, R. R.;
Salahpour, A. In-vivo pharmacology of Trace-Amine Associated
Receptor 1. Eur. J. Pharmacol. 2015, 763, 136−142.
(3) Miller, G. M. The Emerging Role of Trace Amine Associated
Receptor 1 in the Functional Regulation of Monoamine Transporters
and Dopaminergic Activity. J. Neurochem. 2011, 116, 164−176.
(4) Revel, F. G.; Meyer, C. A.; Bradaia, A.; Jeanneau, K.; Calcagno,
E.; Andre, C. B.; Haenggi, M.; Miss, M. T.; Galley, G.; Norcross, R. D.;
et al. Brain-Specific Overexpression of Trace Amine-Associated
Receptor 1 Alters Monoaminergic Neurotransmission and Decreases
Sensitivity to Amphetamine. Neuropsychopharmacology 2012, 37,
2580−2592.
(5) Galley, G.; Stalder, H.; Goergler, A.; Hoener, M. C.; Norcross, R.
D. Optimisation of imidazole compounds as selective TAAR1 agonists:
discovery of RO5073012. Bioorg. Med. Chem. Lett. 2012, 22, 5244−
5248.
(6) Wermuth, C. G. Selective optimization of side activities: the
SOSA approach. Drug Discovery Today 2006, 11, 160−164.
(7) Kleinau, G.; Pratzka, J.; Nurnberg, D.; Gruters, A.; Fuhrer-Sakel,
D.; Krude, H.; Kohrle, J.; Schoneberg, T.; Biebermann, H. Differential
modulation of Beta-adrenergic receptor signaling by trace amine-
associated receptor 1 agonists. PLoS One 2011, 6, e27073.
(8) Lam, V. M.; Rodriguez, D.; Zhang, T.; Koh, E. J.; Carlsson, J.;
Salahpour, A. Discovery of trace amine-associated receptor 1 ligands
Metalated Bis-lactimethers of 2,5-Diketopiperazines. Pure Appl. Chem.
1983, 55, 1799−1806.
(19) Galley, G.; Groebke Zbinden, K.; Norcross, R. D.; Stalder, H.
WO Patent 2008092785, 2008.
(20) Revel, F. G.; Moreau, J. L.; Gainetdinov, R. R.; Ferragud, A.;
Velazquez-Sanchez, C.; Sotnikova, T. D.; Morairty, S. R.; Harmeier, A.;
́ ́
Groebke Zbinden, K.; Norcross, R. D.; Bradaia, A.; Kilduff, T. S.;
Biemans, B.; Pouzet, B.; Caron, M. G.; Canales, J. J.; Wallace, T. L.;
Wettstein, J. G.; Hoener, M. C. Trace amine-associated receptor 1
partial agonism reveals novel paradigm for neuropsychiatric
therapeutics. Biol. Psychiatry 2012, 72, 934−942.
(21) Pei, Y.; Lee, J.; Canales, J. J.; Leo, D.; Gainetdinov, R. R.;
Hoener, M. C. Activation of the trace amine-associated receptor 1
prevents relapse to cocaine seeking. Neuropsychopharmacology 2014,
39, 2299−2308.
(22) Kaivosaari, S.; Finel, M.; Koskinen, M. N-Glucuronidation of
drugs and other xenobiotics by human and animal UDP-glucuronosyl-
transferases. Xenobiotica 2011, 41, 652−669.
(23) MCASE (Multiple Computer Automated Structure Evaluation),
(24) Thompson, R. A.; Isin, E. M.; Li, Y.; Weaver, R.; Weidolf, L.;
Wilson, I.; Claesson, A.; Page, K.; Dolgos, H.; Kenna, J. G. Risk
assessment and mitigation strategies for reactive metabolites in drug
discovery and development. Chem.-Biol. Interact. 2011, 192, 65−71.
(25) Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high
throuput screening: parallel artificial membrane permeation assay in
E
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX