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

Journal of Neurochemistry

Volumn 98, Issue 2, 2006, Pages 601-615

  Malherbe, Pari ^a,b   Kratochwil, Nicole ^a   Mühlemann, Andreas ^a   Zenner, Marie Thérèse ^a   Fischer, Christophe ^a   Stahl, Martin ^a   Gerber, Paul R ^a   Jaeschke, Georg ^a   Porter, Richard H P ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Fenobam; Inverse agonist; Metabotropic glutamate receptor; MPEP; Pharmacophore modelling; Phosphoinositide hydrolysis

Indexed keywords

2 METHYL 6 (2 PHENYLVINYL)PYRIDINE; ALANINE; ARGININE; FENOBAM; INOSITOL PHOSPHATE; LEUCINE; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR AGONIST; METABOTROPIC RECEPTOR ANTAGONIST; PHENYLALANINE; PHOSPHATIDYLINOSITIDE; PROLINE; QUISQUALIC ACID; SERINE; THREONINE; TRYPTOPHAN; TYROSINE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ARTICLE; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; GENE MUTATION; HUMAN; HUMAN CELL; HYDROLYSIS; NUCLEOTIDE SEQUENCE; PHARMACOPHORE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; RECEPTOR BINDING; SITE DIRECTED MUTAGENESIS;

BINDING SITES; CALCIUM; CELL LINE; CELL MEMBRANE; CELLS, CULTURED; EXCITATORY AMINO ACID ANTAGONISTS; FLUOROMETRY; HUMANS; IMIDAZOLES; INOSITOL PHOSPHATES; MODELS, MOLECULAR; MUTATION; PLASMIDS; PYRIDINES; QUISQUALIC ACID; RECEPTORS, METABOTROPIC GLUTAMATE; THIAZOLES;

EID: 33746484507     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/j.1471-4159.2006.03886.x     Document Type: Article

References (40)

1. Ango F., Prezeau L., Muller T., Tu J. C., Xiao B., Worley P. F., Pin J. P., Bockaert J. and Fagni L. (2001 ) Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962-965.
2. Ballesteros J. A. and Weinstein H. (1995) Integrated methods for construction three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Meth. Neurosci. 25, 366-428.
3. Ballesteros J. A., Shi L. and Javitch J. A. (2001a) Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol. Pharmacol. 60, 1-19.
4. Ballesteros J. A., Jensen A. D., Liapakis G., Rasmussen S. G., Shi L., Gether U. and Javitch J. A. (2001b) Activation of the β2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J. Biol. Chem. 276, 29171-29177.
5. Bordi F. and Ugolini A. (1999) Group I metabotropic glutamate receptors: implications for brain diseases. Prog. Neurobiol. 59, 55-79.
6. Carroll F. Y., Stolle A., Beart P. M. et al. (2001) BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol. Pharmacol. 59, 965-973.
7. Cosford N. D., Tehrani L., Roppe J. et al. (2003) 3-[(2-Methyl-1,3- thiazol-4-yl) ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J. Med. Chem. 46, 204-206.
8. Gasparini F., Kuhn R. and Pin J.-P. (2002) Allosteric modulators of group I metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr. Opin. Pharmacol. 2, 43-49.
9. Goldberg M. E., Salama A. I., Patel J. B. and Malick J. B. (1983) Novel non-benzodiazepine anxiolytics. Neuropharmacology 22, 1499-1504.
10. Goudet C., Gaven F. Kniazeff J., Vol C., Liu J., Cohen-Gonsaud M., Acher F., Prezeau L. and Pin J. P. (2004). Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc. Natl Acad. Sci. USA 101, 378-383.
11. Hunkeler W. and Kyburz E. (1980) Urea derivatives. European Patent Application, EP 0016371, 1-21.
12. Joubert L., Claeysen S., Sebben M., Bessis A. S., Clark R. D., Martin R. S., Bockaert J. and Dumuis A. (2002) A 5-HT4 receptor transmembrane network implicated in the activity of inverse agonists but not agonists. J. Biol. Chem. 277, 25 502-25 511.
13. Kew J. N. (2004) Positive and negative allosteric modulation of metabotropic glutamate receptors: emerging therapeutic potential. Pharmacol. Ther. 104, 233-244.
14. Knoflach F., Mutel V., Jolidon S., Kew J. N. C., Malherbe P., Vieira E., Wichmann J. and Kemp J. A. (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc. Natl Acad. Sci. USA 98, 13 402-13 407.
15. Kratochwil N. A., Malherbe P., Lindemann L., Ebeling M., Hoener M. C., Muhlemann A., Porter R. H., Stahl M. and Gerber P. R. (2005) An automated system for the analysis of G protein-coupled receptor transmembrane binding pockets: alignment, receptor-based pharmacophores, and their application. J. Chem. Inf. Model 45, 1324-1336.
16. Kunishima N., Shimada Y., Tsuji Y., Sato T., Yamamoto M., Kumasaka T., Nakanishi S., Jingami H. and Morikawa K. (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971-977.
17. Litschig S., Gasparini F., Rueegg D., Stoehr N., Flor P. J., Vranesic I., Prezeau L., Pin J. P., Thomsen C. and Kuhn R. (1999) CPCCOEt, a non-competitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol. Pharmacol. 55, 453-461.
18. Malherbe P., Knoflach F., Broger C., Ohresser S., Kratzeisen C., Adam G., Stadler H., Kemp J. A. and Mutel V. (2001) Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor. Mol. Pharmacol. 60, 944-954.
19. Malherbe P., Kratochwil N., Zenner M. T., Piussi J., Diener C., Kratzeisen C., Fischer C. and Porter R. H. (2003a) 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.
20. Malherbe P., Kratochwil N., Knoflach F., Zenner M. T., Kew J. N., Kratzeisen C., Maerki H. P., Adam G. and Mutel V. (2003b) Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, non-competitive antagonist of the metabotropic glutamate 1 receptor. J. Biol. Chem. 278, 8340-8347.
21. Miedlich S. U., Gama L., Seuwen K., Wolf R. M. and Breitwieser G. E. (2004) Homology modeling of the transmembrane domain of the human calcium sensing receptor and localization of an allosteric binding site. J. Biol. Chem. 279, 7254-7263.
22. Muhlemann A., Diener C., Fischer C., Piussi J., Stucki A. and Porter R. H. (2005) Constitutive activity modulation of human metabotropic glutamate 5a receptors in HEK293 cells: a role for key aminoterminal cysteine residues. Br. J. Pharmacol. 144, 1118-1125.
23. Muhlemann A., Ward N. A., Kratochwil N., Diener C., Fischer C., Stucki A., Jaeschke G., Malherbe P. and Porter R. H. (2006) 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.
24. Mutel V. (2002) Therapeutic potential of non-competitive, subtype-selective metabotropic glutamate receptor ligands. Expert Opin. Ther. Patents 12, 1845-1852.
25. Nicoletti F., Bruno V., Copani A., Casabona G. and Knopfel T. (1996) Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders? Trends Neurosci. 19, 267-271.
26. Pagano A., Ruegg D., Litschig S. et al. (2000) 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, 33 750-33 758.
27. Palczewski K., Kumasaka T., Hori T. et al. (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739-745.
28. Pecknold J. C., McClure D. J., Appeltauer L., Wrzesinski L. and Allan T. (1982) Treatment of anxiety using fenobam (a non-benzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J. Clin. Psychopharmacol. 2, 129-133.
29. 2+-sensing receptor. J. Biol. Chem. 278, 49 487-49 494.
30. 2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J. Biol. Chem. 279, 18 990-18 997.
31. Pin J. P. and Acher F. (2002) The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr. Drug Target CNS Neurol. Disord. 1, 297-317.
32. Pin J. P., Galvez T. and Prezeau L. (2003) Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol. Ther. 98, 325-354.
33. 2C receptors in CHO-K1 cells. Br. J. Pharmacol. 128, 13-20.
34. Porter R. H., Jaeschke G., Spooren W. et al. (2005) Fenobam: a clinically validated non-benzodiazepine anxiolytic is a potent, selective, and non-competitive mGlu5 receptor antagonist with inverse agonist activity. J. Pharmacol. Exp. Ther. 315, 711-721.
35. Prezeau L., Gomeza J., Ahern S., Mary S., Galvez T., Bockaert J. and Pin J. P. (1996) Changes in the carboxyl-terminal domain of metabotropic glutamate receptor 1 by alternative splicing generate receptors with differing agonist-independent activity. Mol. Pharmacol. 49, 422-429.
36. Sheikh S. P., Zvyaga T. A., Lichtarge O., Sakmar T. P. and Bourne H. R. (1996) Rhodopsin activation blocked by metal-ion-binding sites linking transmembrane helices C and F. Nature 383, 347-350.
37. Sheikh S. P., Vilardarga J. P., Baranski T. J., Lichtarge O., Iiri T., Meng E. C., Nissenson R. A. and Bourne H. R. (1999) Similar structures and shared switch mechanisms of the β2-adrenoceptor and the parathyroid hormone receptor. Zn(II) bridges between helices III and VI block activation. J. Biol Chem. 274, 17 033-17 041.
38. Spooren W. P., Gasparini F., Salt T. E. and Kuhn R. (2001) Novel allosteric antagonists shed light on mglu(5) receptors and CNS disorders. Trends Pharmacol. Sci. 22, 331-337.
39. Swanson C. J., Bures M., Johnson M. P., Linden A. M., Monn J. A. and Schoepp D. D. (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat. Rev. Drug Discov. 4, 131-144.
40. Teller D. C., Okada T., Behnke C. A., Palczewski K. and Stenkamp R. E. (2001) Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochemistry 40, 7761-7772.