Selective negative allosteric modulation of metabotropic glutamate receptors - A structural perspective of ligands and mutants

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Harpsøe, Kasper ^a   Isberg, Vignir ^a   Tehan, Benjamin G ^b   Weiss, Dahlia ^b   Arsova, Angela ^a   Marshall, Fiona H ^b   Bräuner Osborne, Hans ^a   Gloriam, David E ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b Heptares Therapeutics Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

LIGAND; METABOTROPIC RECEPTOR; PROTEIN BINDING;

ALLOSTERISM; BINDING SITE; CHEMISTRY; CONFORMATION; GENETICS; HUMAN; METABOLISM; MOLECULAR MODEL; MUTATION; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; BINDING SITES; HUMANS; LIGANDS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MUTATION; PROTEIN BINDING; RECEPTORS, METABOTROPIC GLUTAMATE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84941578608     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep13869     Document Type: Review

References (62)

1. Nicoletti, F. et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60, 1017-1041 (2011).
2. Doumazane, E. et al. A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J. 25, 66-77 (2011).
3. Mølck, C. et al. mGluR5: Exploration of Orthosteric and Allosteric Ligand Binding Pockets and Their Applications to Drug Discovery. Neurochem. Res. 39, 1862-1875 (2014).
4. Niswender, C. M. & Conn, P. J. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50, 295-322 (2010).
5. Yin, S. & Niswender, C. M. Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cell. Signal. 26, 2284-2297 (2014).
6. Goudet, C. et al. A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J. 26, 1682-1693 (2012).
7. Ahmadian, H. et al. (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors. J. Med. Chem. 40, 3700-3705 (1997).
8. Wellendorph, P. & Brauner-Osborne, H. Molecular basis for amino acid sensing by family C G-protein-coupled receptors. Br. J. Pharmacol. 156, 869-884 (2009).
9. Wu, H. et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344, 58-64 (2014).
10. Trabanco, A. A. & Cid, J. M. mGluR2 positive allosteric modulators: a patent review (2009 - present). Expert Opin. Ther. Pat. 23, 629-647 (2013).
11. Celanire, S. & Campo, B. Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders. Expert Opin. Drug Discov. 7, 261-280 (2012).
12. Lindsley, C. W. & Hopkins, C. R. Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinsons disease: historical perspective and review of the patent literature. Expert Opin. Ther. Pat. 22, 461-481 (2012).
13. Jaeschke, G., Wettstein, J. G., Nordquist, R. E. & Spooren, W. mGlu5 receptor antagonists and their therapeutic potential. Expert Opin. Ther. Pat. 18, 123-142 (2008).
14. Emmitte, K. A. mGlu5 negative allosteric modulators: a patent review (2010-2012). Expert Opin. Ther. Pat. 23, 393-408 (2013).
15. Gregory, K. J., Dong, E. N., Meiler, J. & Conn, P. J. Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology 60, 66-81 (2011).
16. Nickols, H. H. & Conn, P. J. Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol. Dis. 61, 55-71 (2014).
17. Agarwal, P., Sanseau, P. & Cardon, L. R. Novelty in the target landscape of the pharmaceutical industry. Nat. Rev. Drug Discov. 12, 575-576 (2013).
18. Sasikumar, T. K. et al. A-ring modifications on the triazafluorenone core structure and their mGluR1 antagonist properties. Bioorg. Med. Chem. Lett. 20, 2474-2477 (2010).
19. Wenthur, C. J. et al. Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM). J. Med. Chem. 56, 5208-5212 (2013).
20. Kalinichev, M. et al. ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization. J. Pharmacol. Exp. Ther. 344, 624-636 (2013).
21. Nakamura, M. et al. Isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. Bioorg. Med. Chem. Lett. 20, 726-729 (2010).
22. Mathiesen, J. M., Svendsen, N., Brauner-Osborne, H., Thomsen, C. & Ramirez, M. T. Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br. J. Pharmacol. 138, 1026-1030 (2003).
23. Anighoro, A., Bajorath, J. & Rastelli, G. Polypharmacology: challenges and opportunities in drug discovery. J. Med. Chem. 57, 7874-7887 (2014).
24. Mølck, C. et al. Pharmacological characterization and modeling of the binding sites of novel 1,3-bis(pyridinylethynyl)benzenes as metabotropic glutamate receptor 5-selective negative allosteric modulators. Mol. Pharmacol. 82, 929-937 (2012).
25. Dalton, J. A., Gomez-Santacana, X., Llebaria, A. & Giraldo, J. Computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (in)activation. J. Chem. Inf. Model. 54, 1476-1487 (2014).
26. Gregory, K. J. et al. Probing the metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology. Mol. Pharmacol. 83, 991-1006 (2013).
27. Zhang, L. et al. Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1Hpyrazolo-[ 3,4-b]pyra zine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator. J. Med. Chem. 57, 861-877 (2014).
28. Malherbe, P. et al. Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP. J. Neurochem. 98, 601-615 (2006).
29. Lundstrom, L. et al. Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators. Br. J. Pharmacol. 164, 521-537 (2011).
30. Pagano, A. et al. The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b] chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors. J. Biol. Chem. 275, 33750-33758 (2000).
31. Noeske, T. et al. Synergism of virtual screening and medicinal chemistry: identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1. Bioorg. Med. Chem. 17, 5708-5715 (2009).
32. Dore, A. S. et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511, 557-562 (2014).
33. Suzuki, G. et al. In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. J. Pharmacol. Exp. Ther. 323, 147-156 (2007).
34. Fukuda, J. et al. Identification of a novel transmembrane domain involved in the negative modulation of mGluR1 using a newly discovered allosteric mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one. Neuropharmacology 57, 438-445 (2009).
35. Malherbe, P. et al. Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, noncompetitive antagonist of the metabotropic glutamate 1 receptor. J. Biol. Chem. 278, 8340-8347 (2003).
36. Gregory, K. J. et al. Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site. ACS Chem. Neurosci. 5, 282-295 (2014).
37. Wheatley, M. et al. Lifting the lid on GPCRs: the role of extracellular loops. Br. J. Pharmacol. 165, 1688-1703 (2012).
38. Malherbe, P. et al. Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine. Mol. Pharmacol. 64, 823-832 (2003).
39. Farinha, A. et al. Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2. Br. J. Pharmacol. 172, 2383-2396 (2015).
40. Rovira, X. et al. Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J. 29, 116-130 (2015).
41. Turlington, M. et al. Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan- 3-yl)picolinamide (ML254). J. Med. Chem. 56, 7976-7996 (2013).
42. Muhlemann, A. et al. Determination of key amino acids implicated in the actions of allosteric modulation by 3,3′-difluorobenzaldazine on rat mGlu5 receptors. Eur. J. Pharmacol. 529, 95-104 (2006).
43. OBrien, J. A. et al. A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol. Pharmacol. 64, 731-740 (2003).
44. Engers, D. W. et al. Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273. ChemMedChem 4, 505-511 (2009).
45. Sharma, S., Rodriguez, A. L., Conn, P. J. & Lindsley, C. W. Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold. Bioorg. Med. Chem. Lett. 18, 4098-4101 (2008).
46. Wood, M. R., Hopkins, C. R., Brogan, J. T., Conn, P. J. & Lindsley, C. W. "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry 50, 2403-2410 (2011).
47. Sams, A. G., Mikkelsen, G. K., Brodbeck, R. M., Pu, X. & Ritzen, A. Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype. Bioorg. Med. Chem. Lett. 21, 3407-3410 (2011).
48. Vanejevs, M. et al. Positive and negative modulation of group I metabotropic glutamate receptors. J. Med. Chem. 51, 634-647 (2008).
49. Mason, J. et al. High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks. In Silico Pharmacol. 1, 23 (2013).
50. Jacobson, K. A. & Costanzi, S. New insights for drug design from the X-ray crystallographic structures of G-protein-coupled receptors. Mol. Pharmacol. 82, 361-371 (2012).
51. Congreve, M., Langmead, C. J., Mason, J. S. & Marshall, F. H. Progress in structure based drug design for G protein-coupled receptors. J. Med. Chem. 54, 4283-4311 (2011).
52. Phatak, S. S., Gatica, E. A. & Cavasotto, C. N. Ligand-steered modeling and docking: A benchmarking study in class A G-proteincoupled receptors. J. Chem. Inf. Model. 50, 2119-2128 (2010).
53. Vilar, S. et al. Docking-based virtual screening for ligands of G protein-coupled receptors: Not only crystal structures but also in silico models. J. Mol. Graph. Model. 29, 614-623 (2011).
54. Kruse, A. C. et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504, 101-106 (2013).
55. Schwartz, T. W., Frimurer, T. M., Holst, B., Rosenkilde, M. M. & Elling, C. E. Molecular mechanism of 7TM receptor activation- -a global toggle switch model. Annu. Rev. Pharmacol. Toxicol. 46, 481-519 (2006).
56. Tehan, B. G., Bortolato, A., Blaney, F. E., Weir, M. P. & Mason, J. S. Unifying family A GPCR theories of activation. Pharmacol. Ther. 143, 51-60 (2014).
57. Webb, B. & Sali, A. Comparative Protein Structure Modeling Using MODELLER. Curr. Protoc. Bioinformatics 47, 5 6 1-5 6 32 (2014).
58. Berman, H. M. et al. The Protein Data Bank. Nucleic Acids Res 28, 235-242 (2000).
59. Larkin, M. A. et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947-2948 (2007).
60. Isberg, V. et al. Generic GPCR residue numbers - aligning topology maps while minding the gaps. Trends Pharmacol. Sci. 36, 22-31 (2015).
61. Isberg, V. et al. GPCRDB: an information system for G protein-coupled receptors. Nucleic. Acids Res. 42, D422-425 (2014).
62. Pin, J. P., Galvez, T. & Prezeau, L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol. Ther. 98, 325-354 (2003).