Structural Basis for (S)-3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu8 Receptor

Chen, Qi; Ho, Joseph D.; Ashok, Sheela; Vargas, Michelle C.; Wang, Jing; Atwell, Shane; Bures, Mark; Schkeryantz, Jeffery M.; Monn, James A.; Hao, Junliang

doi:10.1021/acs.jmedchem.8b01120

Structural Basis for (S)-3,4-Dicarboxyphenylglycine (DCPG) As a Potent and Subtype Selective Agonist of the mGlu₈ Receptor

Journal Article · Fri Oct 26 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b01120· OSTI ID:1506531

Chen, Qi ^[1]; Ho, Joseph D. ^[1]; Ashok, Sheela ^[1]; Vargas, Michelle C. ^[1]; Wang, Jing ^[1]; Atwell, Shane ^[1]; Bures, Mark ^[1]; Schkeryantz, Jeffery M. ^[1]; Monn, James A. ^[1]; ^[1]

Eli Lilly and Company, Indianapolis, IN (United States)

(S)-3,4-Dicarboxyphenylglycine (DCPG) was first reported in 2001 as a potent orthosteric agonist with high subtype selectivity for the mGlu8 receptor, but the structural basis for its high selectivity is not well understood. Herein, we have solved a cocrystal structure of recombinant human mGlu8 amino terminal domain (ATD) protein bound to (S)-DCPG, which possesses the largest lobe opening angle observed to date among known agonist-bound mGlu ATD crystal structures. The binding conformation of (S)-DCPG observed in the crystal structure is significantly different from that in the homology model built from an L-glutamate-bound rat mGlu1 ATD crystal structure, which has a smaller lobe opening angle. This highlights the importance of considering various lobe opening angles when modeling mGlu ATD–ligand complex. New homology models of other mGlu receptors based on the (S)-DCPG-bound mGlu8 ATD crystal structure were explored to rationalize (S)-DCPG’s high mGlu8 receptor subtype selectivity.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Eli Lilly and Company; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1506531

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (56)

Ionotropic and metabotropic glutamate receptor structure and pharmacology Kew, James N. C.; Kemp, John A. Psychopharmacology, Vol. 179, Issue 1 https://doi.org/10.1007/s00213-005-2200-z	journal	February 2005
The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia Ponnazhagan, Ranjani; Harms, Ashley S.; Thome, Aaron D. Journal of Neuroimmune Pharmacology, Vol. 11, Issue 2 https://doi.org/10.1007/s11481-016-9655-z	journal	February 2016
(S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord Thomas, Nicola K.; Wright, Rebecca A.; Howson, Patrick A. Neuropharmacology, Vol. 40, Issue 3 https://doi.org/10.1016/S0028-3908(00)00169-6	journal	March 2001
Anticonvulsant activity of 3,4-dicarboxyphenylglycines in DBA/2 mice Moldrich, Randal X.; Beart, Philip M.; Jane, David E. Neuropharmacology, Vol. 40, Issue 5 https://doi.org/10.1016/S0028-3908(01)00002-8	journal	April 2001
Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor Linden, A. -M; Johnson, B. G.; Peters, S. C. Neuropharmacology, Vol. 43, Issue 2 https://doi.org/10.1016/S0028-3908(02)00079-5	journal	August 2002
Pharmacological agents acting at subtypes of metabotropic glutamate receptors Schoepp, Darryle D.; Jane, David E.; Monn, James A. Neuropharmacology, Vol. 38, Issue 10 https://doi.org/10.1016/S0028-3908(99)00092-1	journal	October 1999
Acute pharmacological modulation of mGluR8 reduces measures of anxiety Duvoisin, Robert M.; Pfankuch, Tim; Wilson, Julie M. Behavioural Brain Research, Vol. 212, Issue 2 https://doi.org/10.1016/j.bbr.2010.04.006	journal	October 2010
An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction East, Stephen P.; Bamford, Samantha; Dietz, Matthias G. A. Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 16 https://doi.org/10.1016/j.bmcl.2010.06.078	journal	August 2010
Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS) Engers, Darren W.; Gentry, Patrick R.; Williams, Richard Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 17 https://doi.org/10.1016/j.bmcl.2010.07.007	journal	September 2010
Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: Unexpected ‘molecular switch’ from a closely related mGlu4 positive allosteric modulator Utley, Thomas; Haddenham, Dustin; Salovich, James M. Bioorganic & Medicinal Chemistry Letters, Vol. 21, Issue 23 https://doi.org/10.1016/j.bmcl.2011.09.131	journal	December 2011
4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators Jimenez, Hermogenes N.; Liu, Kevin G.; Hong, Sang-Phyo Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 9 https://doi.org/10.1016/j.bmcl.2012.03.032	journal	May 2012
Discovery and characterization of a novel series of N -phenylsulfonyl-1 H -pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu 4 ) Gogliotti, Rocco D.; Blobaum, Anna L.; Morrison, Ryan M. Bioorganic & Medicinal Chemistry Letters, Vol. 26, Issue 13 https://doi.org/10.1016/j.bmcl.2016.05.029	journal	July 2016
Determination of L-AP4-bound human mGlu8 receptor amino terminal domain structure and the molecular basis for L-AP4’s group III mGlu receptor functional potency and selectivity Schkeryantz, Jeffery M.; Chen, Qi; Ho, Joseph D. Bioorganic & Medicinal Chemistry Letters, Vol. 28, Issue 4 https://doi.org/10.1016/j.bmcl.2018.01.037	journal	February 2018
Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia Robbins, Melanie J.; Starr, Kathryn R.; Honey, Andy Brain Research, Vol. 1152 https://doi.org/10.1016/j.brainres.2007.03.028	journal	June 2007
Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation Changeux, Jean-Pierre; Christopoulos, Arthur Cell, Vol. 166, Issue 5 https://doi.org/10.1016/j.cell.2016.08.015	journal	August 2016
Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG Bäckström, Pia; Hyytiä, Petri European Journal of Pharmacology, Vol. 528, Issue 1-3 https://doi.org/10.1016/j.ejphar.2005.10.051	journal	December 2005
Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on inflammatory and neuropathic pain in mice Marabese, I.; de Novellis, V.; Palazzo, E. Neuropharmacology, Vol. 52, Issue 2 https://doi.org/10.1016/j.neuropharm.2006.04.006	journal	February 2007
Constitutive endocytosis of the metabotropic glutamate receptor mGluR7 is clathrin-independent Lavezzari, Gabriela; Roche, Katherine W. Neuropharmacology, Vol. 52, Issue 1 https://doi.org/10.1016/j.neuropharm.2006.07.011	journal	January 2007
Anticonvulsant and neuroprotective effect of (S)-3,4-dicarboxyphenylglycine against seizures induced in immature rats by homocysteic acid Folbergrová, Jaroslava; Druga, Rastislav; Haugvicová, Renata Neuropharmacology, Vol. 54, Issue 4 https://doi.org/10.1016/j.neuropharm.2007.11.015	journal	March 2008
Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu4 receptor Sławińska, Anna; Wierońska, Joanna M.; Stachowicz, Katarzyna Neuropharmacology, Vol. 66 https://doi.org/10.1016/j.neuropharm.2012.05.001	journal	March 2013
Metabotropic glutamate receptors and neurodegenerative diseases Ribeiro, Fabiola M.; Vieira, Luciene B.; Pires, Rita G. W. Pharmacological Research, Vol. 115 https://doi.org/10.1016/j.phrs.2016.11.013	journal	January 2017
Identification of Allosteric Modulators of Metabotropic Glutamate 7 Receptor Using Proteochemometric Modeling Tresadern, Gary; Trabanco, Andres A.; Pérez-Benito, Laura Journal of Chemical Information and Modeling, Vol. 57, Issue 12 https://doi.org/10.1021/acs.jcim.7b00338	journal	December 2017
Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu ₅ Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile) Christopher, John A.; Aves, Sarah J.; Bennett, Kirstie A. Journal of Medicinal Chemistry, Vol. 58, Issue 16 https://doi.org/10.1021/acs.jmedchem.5b00892	journal	August 2015
Synthesis and Pharmacological Characterization of C 4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 R ,2 S ,4 R ,5 R ,6 R )-2-Amino-4-(1 H -1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu ₂ Receptor Agonist Monn, James A.; Prieto, Lourdes; Taboada, Lorena Journal of Medicinal Chemistry, Vol. 58, Issue 18 https://doi.org/10.1021/acs.jmedchem.5b01124	journal	September 2015
Discovery of (1 S ,2 R ,3 S ,4 S ,5 R ,6 R )-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 Chappell, Mark D.; Li, Renhua; Smith, Stephon C. Journal of Medicinal Chemistry, Vol. 59, Issue 24 https://doi.org/10.1021/acs.jmedchem.6b01119	journal	December 2016
Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites Selvam, Chelliah; Lemasson, Isabelle A.; Brabet, Isabelle Journal of Medicinal Chemistry, Vol. 61, Issue 5 https://doi.org/10.1021/acs.jmedchem.7b01438	journal	January 2018
Synthesis and Pharmacological Characterization of C4 _β -Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S, 2 S, 4 S, 5 R, 6 S )-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu ₃ Receptor Agonist Monn, James A.; Henry, Steven S.; Massey, Steven M. Journal of Medicinal Chemistry, Vol. 61, Issue 6 https://doi.org/10.1021/acs.jmedchem.7b01481	journal	January 2018
Discovery, Synthesis, and Preclinical Characterization of N -(3-Chloro-4-fluorophenyl)-1 H -pyrazolo[4,3- b ]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu ₄ ) Engers, Darren W.; Blobaum, Anna L.; Gogliotti, Rocco D. ACS Chemical Neuroscience, Vol. 7, Issue 9 https://doi.org/10.1021/acschemneuro.6b00035	journal	May 2016
Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu _2/4 Heteromers Niswender, Colleen M.; Jones, Carrie K.; Lin, Xin ACS Chemical Neuroscience, Vol. 7, Issue 9 https://doi.org/10.1021/acschemneuro.6b00036	journal	August 2016
Discovery of VU6005649, a CNS Penetrant mGlu _7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5- a ]pyrimidines Abe, Masahito; Seto, Mabel; Gogliotti, Rocco G. ACS Medicinal Chemistry Letters, Vol. 8, Issue 10 https://doi.org/10.1021/acsmedchemlett.7b00317	journal	September 2017
Identification of Positive Allosteric Modulators VU0155094 (ML397) and VU0422288 (ML396) Reveals New Insights into the Biology of Metabotropic Glutamate Receptor 7 Jalan-Sakrikar, Nidhi; Field, Julie R.; Klar, Rebecca ACS Chemical Neuroscience, Vol. 5, Issue 12 https://doi.org/10.1021/cn500153z	journal	September 2014
Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B. Journal of Medicinal Chemistry, Vol. 47, Issue 7 https://doi.org/10.1021/jm0306430	journal	March 2004
Novel Procedure for Modeling Ligand/Receptor Induced Fit Effects Sherman, Woody; Day, Tyler; Jacobson, Matthew P. Journal of Medicinal Chemistry, Vol. 49, Issue 2 https://doi.org/10.1021/jm050540c	journal	January 2006
Tricyclic Thiazolopyrazole Derivatives as Metabotropic Glutamate Receptor 4 Positive Allosteric Modulators Hong, Sang-Phyo; Liu, Kevin G.; Ma, Gil Journal of Medicinal Chemistry, Vol. 54, Issue 14 https://doi.org/10.1021/jm200290z	journal	July 2011
Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1 S ,2 S ,5 R ,6 S -2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures Monn, James A.; Prieto, Lourdes; Taboada, Lorena Journal of Medicinal Chemistry, Vol. 58, Issue 4 https://doi.org/10.1021/jm501612y	journal	February 2015
Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor Kunishima, Naoki; Shimada, Yoshimi; Tsuji, Yuji Nature, Vol. 407, Issue 6807 https://doi.org/10.1038/35039564	journal	October 2000
Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain Doré, Andrew S.; Okrasa, Krzysztof; Patel, Jayesh C. Nature, Vol. 511, Issue 7511 https://doi.org/10.1038/nature13396	journal	July 2014
Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone Wang, Sheng; Che, Tao; Levit, Anat Nature, Vol. 555, Issue 7695 https://doi.org/10.1038/nature25758	journal	January 2018
Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+ Tsuchiya, D.; Kunishima, N.; Kamiya, N. Proceedings of the National Academy of Sciences, Vol. 99, Issue 5 https://doi.org/10.1073/pnas.052708599	journal	February 2002
Structures of the extracellular regions of the group II/III metabotropic glutamate receptors Muto, T.; Tsuchiya, D.; Morikawa, K. Proceedings of the National Academy of Sciences, Vol. 104, Issue 10 https://doi.org/10.1073/pnas.0611577104	journal	February 2007
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Scaling and assessment of data quality Evans, Philip Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 1, p. 72-82 https://doi.org/10.1107/S0907444905036693	journal	December 2005
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
REFMAC 5 for the refinement of macromolecular crystal structures Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911001314	journal	March 2011
Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8: Anxiety and weight gain in mGluR8-/- mice Duvoisin, Robert M.; Zhang, Connie; Pfankuch, Timothy F. European Journal of Neuroscience, Vol. 22, Issue 2 https://doi.org/10.1111/j.1460-9568.2005.04210.x	journal	July 2005
The effect of mGlu ₈ deficiency in animal models of psychiatric diseases Fendt, M.; Bürki, H.; Imobersteg, S. Genes, Brain and Behavior, Vol. 9, Issue 1 https://doi.org/10.1111/j.1601-183X.2009.00532.x	journal	February 2010
ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization Kalinichev, Mikhail; Rouillier, Mélanie; Girard, Francoise Journal of Pharmacology and Experimental Therapeutics, Vol. 344, Issue 3 https://doi.org/10.1124/jpet.112.200915	journal	December 2012
Molecular Basis for the Differential Agonist Affinities of Group III Metabotropic Glutamate Receptors Rosemond, Erica; Wang, Minghua; Yao, Yi Molecular Pharmacology, Vol. 66, Issue 4 https://doi.org/10.1124/mol.104.002956	journal	July 2004
Glutamate Receptor Ion Channels: Structure, Regulation, and Function Traynelis, Stephen F.; Wollmuth, Lonnie P.; McBain, Chris J. Pharmacological Reviews, Vol. 62, Issue 3 https://doi.org/10.1124/pr.109.002451	journal	August 2010
Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator Wu, Huixian; Wang, Chong; Gregory, Karen J. Science, Vol. 344, Issue 6179 https://doi.org/10.1126/science.1249489	journal	March 2014
Allosteric Modulation of G Protein–Coupled Receptors May, Lauren T.; Leach, Katie; Sexton, Patrick M. Annual Review of Pharmacology and Toxicology, Vol. 47, Issue 1 https://doi.org/10.1146/annurev.pharmtox.47.120505.105159	journal	February 2007
Constitutive activity of metabotropic glutamate receptor 7 Kammermeier, Paul J. BMC Neuroscience, Vol. 16, Issue 1 https://doi.org/10.1186/s12868-015-0154-6	journal	March 2015
Reconstruction of 3D structures of MET antibodies from electron microscopy 2D class averages Chen, Qi; Vieth, Michal; Timm, David E. PLOS ONE, Vol. 12, Issue 4 https://doi.org/10.1371/journal.pone.0175758	journal	April 2017
Metabotropic Glutamate Receptors in Central Nervous System Diseases V. Golubeva, Anna; D. Moloney, Rachel; M. O';Connor, Richard Current Drug Targets, Vol. 17, Issue 5 https://doi.org/10.2174/1389450116666150316224011	journal	March 2016

Cited By (1)

Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors Llinas del Torrent, Claudia; Pérez-Benito, Laura; Tresadern, Gary Molecules, Vol. 24, Issue 6 https://doi.org/10.3390/molecules24061098	journal	March 2019

Similar Records

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 Article · Thu Nov 10 19:00:00 EST 2016 · Journal of Medicinal Chemistry · OSTI ID:1340719

Determination of L-AP4-bound human mGlu8 receptor amino terminal domain structure and the molecular basis for L-AP4’s group III mGlu receptor functional potency and selectivity

Journal Article · Wed Jan 31 23:00:00 EST 2018 · Bioorganic and Medicinal Chemistry Letters · OSTI ID:1432884

The N-terminal domain of GluR6-subtype glutamate receptor ion channels

Journal Article · Fri Sep 25 00:00:00 EDT 2009 · Nat. Struct. Mol. Biol. · OSTI ID:1005889

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Chemical structure
Conformation
Crystal structure
Ligands
Receptors