Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity

Journal of Medicinal Chemistry

Volumn 59, Issue 24, 2016, Pages 10974-10993

  Chappell, Mark D ^a   Li, Renhua ^a   Smith, Stephon C ^a   Dressman, Bruce A ^a   Tromiczak, Eric G ^a   Tripp, Allie E ^a   Blanco, Maria Jesus ^a   Vetman, Tatiana ^a   Quimby, Steven J ^a   Matt, James ^a   Britton, Thomas C ^a   Fivush, Adam M ^a   Schkeryantz, Jeffrey M ^a   Mayhugh, Daniel ^a   Erickson, Jon A ^a   Bures, Mark G ^a   Jaramillo, Carlos ^c   Carpintero, Mercedes ^c   Diego, José Eugenio De ^c   Barberis, Mario ^c   Garcia Cerrada, Susana ^c   Soriano, José F ^c   Antonysamy, Stephen ^b   Atwell, Shane ^b   Macewan, Iain ^b   Condon, Bradley ^b   Sougias, Christine ^b   Wang, Jing ^b   Zhang, Aiping ^b   Conners, Kris ^b   Groshong, Chris ^b   Wasserman, Stephen R ^d   Koss, John W ^d   Witkin, Jeffrey M ^b   Li, Xia ^b   Overshiner, Carl ^b   Wafford, Keith A ^b   Seidel, Wesley ^b   Wang, Xu Shan ^b   Heinz, Beverly A ^b   Swanson, Steven ^e   Catlow, John T ^e   Bedwell, David W ^e   Monn, James A ^a   Mitch, Charles H ^a   Ornstein, Paul L ^a   more..

^a Discovery Chemistry Research and Technologies: Medicinal Chemistry   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c Centro de Investigación Básica   (Spain)

^d ARGONNE NATIONAL LABORATORY   (United States)

^e Drug Disposition   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (TERT BUTOXYCARBONYLAMINO) 3 [(4 FLUORO 3 METHYL PHENYL)SULFANYLMETHYL] 4 METHYLSULFONYLOXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLATE; 2 AMINO 3 [(2 FLUOROPHENYL)SULFANYLMETHYL] 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(3 FLUOROPHENYL)SULFANYLMETHYL] 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(3,4 DICHLOROPHENYL)METHYLSULFANYLMETHYL) 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(3,4 DICHLOROPHENYL)SULFANYLMETHYL) 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(3,4 DIFLUOROPHENYL)SULFANYLMETHYL] 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(3,4 DIMETHYLPHENYL)SULFANYLMETHYL] 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(4 FLUORO 3 METHYL PHENYL)SULFANYLMETHYL] 4 (1H 1,2,4 TRIAZOL 3 YLSULFANYL)BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(4 FLUORO 3 METHYL PHENYL)SULFANYLMETHYL] 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 3 [(4 FLUOROPHENYL)SULFANYLMETHYL] 4 HYDROXY BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 4 HYDROXY 3 (ISOPROPYLSULFANYLMETHYL)BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2 AMINO 4 HYDROXY 3 (PHENYLSULFANYLMETHYL)BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 2,4 DIAMINO 3 [(3 FLUORO 4 METHYL PHENYL)SULFANYLMETHYL]BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; 4 ACETAMIDO 2 AMINO 3 [(4 FLUORO 3 METHYLPHENYL)SULFANYLMETHYLPHENYL)SULFANYLMETHYL]BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLIC ACID; ANTIDEPRESSANT AGENT; DI TERT BUTYL 2 (TERT BUTOXYCARBONYLAMINO) 3 [(4 FLUORO 3 METHYL PHENYL)SULFANYLMETHYL] 4 (1H 1,2,4 TRIAZOL 3 YLSULFANYL)BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLATE; DI TERT BUTYL 4 ACETAMIDO 2 (TERT BUTOXYCARBONYLAMINO) 3 [(4 FLUORO 3 METHYL PHENYL)SULFANYLMETHYL]BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLATE; DI TERT BUTYL 4 AMINO 2 (TERT BUTOXYCARBONYLAMINO)3 [(4 FLUORO 3 METHYL PHENYL)SULFANYLMETHYL]BICYCLO[3.1.0]HEXANE 2,6 DICARBOXYLATE; IMIPRAMINE; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG; 2-AMINO-3-((3,4-DIFLUOROPHENYL)SULFANYLMETHYL)-4-HYDROXY-BICYCLO(3.1.0)HEXANE-2,6-DICARBOXYLIC ACID HYDROCHLORIDE; CYCLOHEXANE DERIVATIVE; METABOTROPIC RECEPTOR; METABOTROPIC RECEPTOR 3;

AMINO TERMINAL SEQUENCE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIDEPRESSANT ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; CRYSTALLIZATION; DEPRESSION; DRUG BRAIN LEVEL; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SOLUBILITY; DRUG SYNTHESIS; FORCED SWIM TEST; HUMAN; HUMAN CELL; IC50; MALE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TIME TO MAXIMUM PLASMA CONCENTRATION; UNBOUND FRACTION; ANIMAL; ANIMAL BEHAVIOR; ANTAGONISTS AND INHIBITORS; BRAIN; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG EFFECTS; INBRED MOUSE STRAIN; ISOLATION AND PURIFICATION; MOLECULAR MODEL; MOTOR ACTIVITY; SWIMMING; SYNTHESIS;

ANIMALS; ANTIDEPRESSIVE AGENTS; BEHAVIOR, ANIMAL; BRAIN; CYCLOHEXANES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; HUMANS; MALE; MICE; MICE, INBRED STRAINS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MOTOR ACTIVITY; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP; SWIMMING;

EID: 85007099137     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b01119     Document Type: Article

References (69)

1. Iversen, L. The monoamine hypothesis of depression. In Biology of Depression; Licinio, J., Wong, M. L.; Eds; Wiley-VCH: Weinheim, 2005; pp 71-86.
2. Traynelis, S. F.; Wollmuth, L. P.; McBain, C. J.; Menniti, F. S.; Vance, K. M.; Ogden, K. K.; Hansen, K. B.; Yuan, H.; Myers, S. J.; Dingledine, R. Glutamate receptor ion channels: structure, regulation, and function Pharmacol. Rev. 2010, 62, 405-496 10.1124/pr.109.002451
3. Conn, P. J.; Pin, J.-P. Pharmacology and functions of metabotropic glutamate receptors Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205-237 10.1146/annurev.pharmtox.37.1.205
4. Schoepp, D. E.; Jane, D. E.; Monn, J. A. Pharmacological agents acting at subtypes of metabotropic glutamate receptor Neuropharmacology 1999, 38, 1431-1476 10.1016/S0028-3908(99)00092-1
5. Chaki, S. Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia Eur. J. Pharmacol. 2010, 639, 59-66 10.1016/j.ejphar.2009.12.041
6. Swanson, C. J.; Bures, M.; Johnson, M. P.; Linden, A. M.; Monn, J. A.; Schoepp, D. D. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders Nat. Rev. Drug Discovery 2005, 4, 131-144 10.1038/nrd1630
7. Skolnick, P.; Popik, P.; Trullas, R. Glutamate based antidepressants: 20 years on Trends Pharmacol. Sci. 2009, 30, 563-569 10.1016/j.tips.2009.09.002
8. Sanacora, G.; Zarate, C. A.; Krystal, J. H.; Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders Nat. Rev. Drug Discovery 2008, 7, 426-437 10.1038/nrd2462
9. Witkin, J. M.; Marek, G. J.; Johnson, B. G.; Schoepp, D. D. Metabotropic glutamate receptors in the control of mood disorders CNS Neurol. Disord.: Drug Targets 2007, 6, 87-100 10.2174/187152707780363302
10. Kingston, A. E.; O'Neill, M. J.; Lam, A.; Bales, K. R.; Monn, J. A.; Schoepp, D. D. Neuroprotection by metabotropic glutamate receptor agonists: LY354740, LY379268 and LY389795 Eur. J. Pharmacol. 1999, 377, 155-165 10.1016/S0014-2999(99)00397-0
11. 2/3 agonist in the treatment of generalized anxiety disorder Neuropsychopharmacology 2008, 33, 1603-1610 10.1038/sj.npp.1301531
12. 2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial Nat. Med. 2007, 13, 1102-1107 10.1038/nm1632
13. Stocchi, F.; Rascol, O.; Destee, A.; Hattori, N.; Hauser, R. A.; Lang, A. E.; Poewe, W.; Stacy, M.; Tolosa, E.; Gao, H.; Nagel, J.; Merschhemke, M.; Graf, A.; Kenney, C.; Trenkwalder, C. AFQ056 in parkinson patients with levodopa-induced dyskinesia: 13-week, randomized, dose-finding study Mov. Disord. 2013, 28, 1838-1846 10.1002/mds.25561
14. Gu, G.; Lorrain, D. S.; Wei, H.; Cole, R. L.; Zhang, X.; Daggett, L. P.; Schaffhauser, H.; Bristow, L. J.; Lechner, S. M. Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: implication in emotional responses and central disinhibition Brain Res. 2008, 1197, 47-62 10.1016/j.brainres.2007.12.057
15. 3R in the mouse CNS: differential location relative to pre- and postsynaptic sites Neuroscience 2001, 106, 481-503 10.1016/S0306-4522(01)00305-0
16. Cartmell, J.; Schoepp, D. D. Regulation of neurotransmitter release by metabotropic glutamate receptors J. Neurochem. 2000, 75, 889-907 10.1046/j.1471-4159.2000.0750889.x
17. Schoepp, D. D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system J. Pharmacol. Exp. Ther. 2001, 299, 12-20
18. Spooren, W. P. J. M.; Gasparini, F.; van der Putten, H.; Koller, M.; Nakanishi, S.; Kuhn, R. Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice Eur. J. Pharmacol. 2000, 397, R1-R2 10.1016/S0014-2999(00)00269-7
19. 2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) J. Pharmacol. Exp. Ther. 2008, 326, 209-217 10.1124/jpet.108.136861
20. 3 receptor agonists Mol. Pain 2011, 7, 6-10 10.1186/1744-8069-7-6
21. Govindaiah, G.; Cox, C. L. Metabotropic glutamate receptors differentially regulate GABAergic inhibition in thalamus J. Neurosci. 2006, 26, 13443-13453 10.1523/JNEUROSCI.3578-06.2006
22. Walker, A. G.; Wenthur, C. J.; Xiang, Z.; Rook, J. M.; Emmitte, K. A.; Niswender, C. M.; Lindsley, C. W.; Conn, P. J. Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 1196-1201 10.1073/pnas.1416196112
23. 3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection J. Neurosci. 2007, 27, 8297-8308 10.1523/JNEUROSCI.1889-07.2007
24. 2R Science 1996, 273, 645-647 10.1126/science.273.5275.645
25. Kilbride, J.; Rush, A. M.; Rowan, M. J.; Anwyl, R. Presynaptic group II mGluR inhibition of short-term depression in the medial perforant path of the dentate gyrus in vitro J. Neurophysiol. 2001, 85, 2509-2515
26. Neugebauer, V.; Zinebi, F.; Russell, R.; Gallagher, J. P.; Shinnick-Gallagher, P. Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala J. Neurophysiol. 2000, 84, 759-770
27. 2-/- mice Neuropharmacology 2002, 43, 215-221 10.1016/S0028-3908(02)00084-9
28. 2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure J. Mol. Psychiatry 2013, 1, 1-4 10.1186/2049-9256-1-15
29. 2/3 blockade Int. J. Neuropsychopharmacol. 2012, 15, 429-434 10.1017/S1461145711001702
30. Koike, H.; Fukumoto, K.; Iijima, M.; Chaki, S. Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression Behav. Brain Res. 2013, 238, 48-52 10.1016/j.bbr.2012.10.023
31. 2/3 receptor antagonist and ketamine require AMPA receptor stimulation in the mPFC and subsequent activation of the 5-HT neurons in the DRN Neuropsychopharmacology 2016, 41, 1046-1056 10.1038/npp.2015.233
32. Berman, R. M.; Cappiello, A.; Anand, A.; Oren, D. A.; Heninger, G. R.; Charney, D. S.; Krystal, J. H. Antidepressant effects of ketamine in depressed patients Biol. Psychiatry 2000, 47, 351-354 10.1016/S0006-3223(99)00230-9
33. Zarate, C. A.; Singh, J. B.; Carlson, P. J.; Brutsche, N. E.; Ameli, R.; Luckenbaugh, D. A.; Charney, D. S.; Manji, H. K. A randomized trial of a N-methyl-D-aspartate antagonist in treatment-resistant major depression Arch. Gen. Psychiatry 2006, 63, 856-864 10.1001/archpsyc.63.8.856
34. Mathew, S. J.; Murrough, J. W.; Aan Het Rot, M.; Collins, K. A.; Reich, D. L.; Charney, D. S. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial Int. J. Neuropsychopharmacol. 2010, 13, 71-82 10.1017/S1461145709000169
35. Aan Het Rot, M.; Zarate, C. A.; Charney, D. S.; Mathew, S. J. Ketamine for depression: where do we go from here? Biol. Psychiatry 2012, 72, 537-547 10.1016/j.biopsych.2012.05.003
36. Mathew, S. J.; Shah, A.; Lapidus, K.; Clark, C.; Jarun, N.; Ostermeyer, B.; Murrough, J. W. Ketamine for treatment-resistant unipolar depression: current evidence CNS Drugs 2012, 26, 189-204 10.2165/11599770-000000000-00000
37. Murrough, J. W.; Iosifescu, D. V.; Chang, L. C.; Al Jurdi, R. K.; Green, C. E.; Perez, A. M.; Iqbal, S.; Pillemer, S.; Foulkes, A.; Shah, A.; Charney, D. S.; Mathew, S. J. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial Am. J. Psychiatry 2013, 170, 1134-1142 10.1176/appi.ajp.2013.13030392
38. Ornstein, P. L.; Bleisch, T. J.; Arnold, M. B.; Kennedy, J. H.; Wright, R. A.; Johnson, B. G.; Tizzano, J. P.; Helton, D. R.; Kallman, M. J.; Schoepp, D. D.; Hérin, M. 2-Substituted (2SR)-2-amino-2((1SR, 2SR)-2carboxycyclop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability J. Med. Chem. 1998, 41, 358-378 10.1021/jm970498o
39. Kingston, A. E.; Ornstein, P. L.; Wright, R. A.; Johnson, B. G.; Mayne, N. G.; Burnett, J. P.; Belagaje, R.; Wu, S.; Schoepp, D. D. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors Neuropharmacology 1999, 37, 1-12 10.1016/S0028-3908(97)00191-3
40. Chaki, S.; Yoshikawa, R.; Hirota, S.; Shimazaki, T.; Maeda, M.; Kawashima, N.; Yoshimizu, T.; Yasuhara, A.; Sakagami, K.; Okuyama, S.; Nakanishi, S.; Nakazato, A. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity Neuropharmacology 2004, 46, 457-467 10.1016/j.neuropharm.2003.10.009
41. 2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats Psychopharmacology 2006, 186, 587-593 10.1007/s00213-006-0390-7
42. Pałucha-Poniewiera, A.; Wierońska, J. M.; Brański, P.; Stachowicz, K.; Chaki, S.; Pilc, A. On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039 Psychopharmacology 2010, 212, 523-535 10.1007/s00213-010-1978-5
43. Sheffler, D. J.; Pinkerton, A. B.; Dahl, R.; Markou, A.; Cosford, N.D. P. Recent progress in the synthesis and characterization of group II metabotropic glutamate receptor allosteric modulators ACS Chem. Neurosci. 2011, 2, 382-393 10.1021/cn200008d
44. Katalinic, N.; Lai, R.; Somogyi, A.; Mitchell, P. B.; Glue, P.; Loo, C. K. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects Aust. N. Z. J. Psychiatry 2013, 47, 710-727 10.1177/0004867413486842
45. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.; Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.; Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J. P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. Design, synthesis and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties J. Med. Chem. 1997, 40, 528-537 10.1021/jm9606756
46. Schoepp, D. D.; Johnson, B. G.; Wright, R. A.; Salhoff, C. R.; Mayne, N. G.; Wu, S.; Cockerham, S. L.; Burnett, J. P.; Belegaje, R.; Bleakman, D.; Monn, J. A. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors Neuropharmacology 1997, 36, 1-11 10.1016/S0028-3908(96)00160-8
47. 2/3 receptors J. Med. Chem. 2007, 50, 233-240 10.1021/jm060917u
48. 2/3 receptor agonist: In vitro characterization of LY404039 J. Pharmacol. Exp. Ther. 2007, 321, 308-317 10.1124/jpet.106.110809
49. 2/3 receptor agonist LY404039 in animal models of psychiatric disorders Psychopharmacology 2007, 193, 121-136 10.1007/s00213-007-0758-3
50. 2/3 agonist in the treatment of generalized anxiety disorder Neuropsychopharmacology 2008, 33, 1603-1610 10.1038/sj.npp.1301531
51. 2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial Nat. Med. 2007, 13, 1102-1107 10.1038/nm1632
52. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hao, J.; Reinhard, M.; Bures, M. G.; Heinz, B.; Wang, X.; Carter, J. H.; Getman, B. G.; Stephenson, G. A.; Herin, M.; Catlow, J. T.; Swanson, S.; Johnson, B. G.; McKinzie, D. L.; Henry, S. S. Synthesis and pharmacological characterization of 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: identification of new potent and selective metabotropic glutamate 2/3 receptor agonists J. Med. Chem. 2013, 56, 4442-4455 10.1021/jm4000165
53. Dominguez-Fernandez, C.; Helton, D. R.; Massey, S. M.; Monn, J. A. Preparation of excitatory amino acid receptor antagonists. Eur. Pat. Appl. 774455, 1996.
54. Varie, D. L.; Beck, C. B.; Borders, S. K.; Brady, M. D.; Cronin, J. S.; Ditsworth, T. K.; Hay, D. A.; Hoard, D. W.; Hoying, R. C.; Linder, R. J.; Miller, R. D.; Moher, E. D.; Remacle, J. R.; Rieck, J. A.; Anderson, D. D.; Dodson, P. N.; Forst, M. B; Pierson, D. A.; Turpin, J. A. III. Design, development, and scale-up of a selective meso-epoxide desymmetrizationprocess Org. Process Res. Dev. 2007, 11, 546-559 10.1021/op060225f
55. Bredereck, H.; Simchen, G.; Rebsdat, S.; Kantlehner, W.; Horn, P.; Wahl, R.; Hoffmann, H.; Grieshaber, P. Acid amide reactions. L. Orthoamides. 1. Preparation and properties of amide acetals and aminal esters Chem. Ber. 1968, 101, 41 10.1002/cber.19681010108
56. Corey, E. J.; Bakshi, R. K.; Shibata, S. Highly enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. Mechanism and synthetic implications J. Am. Chem. Soc. 1987, 109, 5551-5553 10.1021/ja00252a056
57. 2]. In Synthesis and Applications of Isotopically Labeled Compounds, Proceedings of the International Symposium, Vol. 8; Dean, D. C.; Filer, C. N.; McCarthy, K. E., Eds.; John Wiley and Sons, Ltd.: Chichester, U.K., 2003; pp 267-270.
58. 3H]-LY459477 autoradiography Neuropharmacology 2013, 66, 89-98 10.1016/j.neuropharm.2012.01.019
59. 3 amino terminal domain structures J. Med. Chem. 2015, 58, 1776-1794 10.1021/jm501612y
60. 2 receptor agonist J. Med. Chem. 2015, 58, 7526-7548 10.1021/acs.jmedchem.5b01124
61. Tanabe, Y.; Masu, M.; Ishii, T.; Shigemoto, R.; Nakanishi, S. A family of metabotropic glutamate receptors Neuron 1992, 8, 169-179 10.1016/0896-6273(92)90118-W
62. Mercier, M. S.; Lodge, D. Group III metabotropic glutamate receptors: pharmacology, physiology and therapeutic potential Neurochem. Res. 2014, 39, 1876-1894 10.1007/s11064-014-1415-y
63. For CEREP assay details, see: http://www.cerep.fr/Cerep/Users/pages/Downloads/pharmacology.asp (accessed September, 17, 2016).
64. Muto, T.; Tsuchiya, D.; Morikawa, K.; Jingami, H. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 3759-3764 10.1073/pnas.0611577104
65. Wernimont, A. K.; Dong, A.; Seitova, A.; Crombet, L.; Khutoreskaya, G.; Edwards, A. M.; Arrowsmith, C. H.; Bountra, C.; Weigelt, J.; Cossar, D.; Dobrovetsky, E. Crystal structure of metabotropic glutamate receptor 3 precursor in presence of LY341495 antagonist. RCSB Protein Data Bank, deposited June 27, 2011; DOI: 10.2210/pdb3sm9/pdb.
66. Molecular Operating Environment (MOE), version 2013.08; Chemical Computing Group, Inc.: Montreal, QC, Canada, 2013.
67. 2/3 receptor antagonist. Neuropharmacology 2016, DOI: 10.1016/j.neuropharm.2015.12.021
68. 2 at the following site: http://www.phosphosite.org (accessed May 15, 2016).
69. 2/3 receptor antagonism CNS Neurol. Disord.: Drug Targets 2013, 12, 554-566 10.2174/18715273113129990079