Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine

Molecular Pharmacology

Volumn 64, Issue 4, 2003, Pages 823-832

  Malherbe, Pari ^a,b   Kratochwil, Nicole ^b   Zenner, Marie Thérèse ^a   Piussi, Jenny ^a   Diener, Catherine ^a   Kratzeisen, Claudia ^a   Fischer, Christophe ^a   Porter, Richard H P ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

1 ETHYL 2 METHYL 6 OXO 4 (1,2,4,5 TETRAHYDROBENZO[D]AZEPIN 3 YL) 1,6 DIHYDROPYRIMIDINE 5 CARBONITRILE; 2 METHYL 6 (PHENYLETHYNYL)PYRIDINE; G PROTEIN COUPLED RECEPTOR; GLUTAMATE RECEPTOR; ION CHANNEL; METABOTROPIC RECEPTOR; RHODOPSIN; UNCLASSIFIED DRUG;

ARTICLE; CALCIUM CELL LEVEL; CALCIUM MOBILIZATION; COMPETITIVE INHIBITION; CRYSTAL STRUCTURE; GENE MUTATION; GENETIC ANALYSIS; HUMAN; HUMAN CELL; MOLECULAR CLONING; MOLECULAR MODEL; NERVE CELL PLASTICITY; NEUROTRANSMITTER RELEASE; POINT MUTATION; PRIORITY JOURNAL; PROTEIN DOMAIN; SITE DIRECTED MUTAGENESIS;

ALLOSTERIC SITE; AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; CALCIUM; CELLS, CULTURED; EXCITATORY AMINO ACID AGONISTS; EXCITATORY AMINO ACID ANTAGONISTS; HUMANS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR SEQUENCE DATA; POINT MUTATION; PROTEIN STRUCTURE, TERTIARY; PYRIDINES; QUISQUALIC ACID; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; RHODOPSIN; SEQUENCE HOMOLOGY, AMINO ACID; TRITIUM;

EID: 0141569326     PISSN: 0026895X     EISSN: None     Source Type: Journal    
DOI: 10.1124/mol.64.4.823     Document Type: Article

References (41)

1. Annoura H, Fukunaga A, Uesugi M, Tatsuoka T, and Horikawa Y (1996) A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropachromen-1a-carboxylates. Bioorg Med Chem Lett 6:763-766.
2. Ballesteros JA, Jensen AD, Liapakis G, Rasmussen SG, Shi L, Gether U, and Javitch JA (2001a) 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.
3. Ballesteros JA, Shi L, and Javitch JA (2001b) 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 JA and Weinstein H (1995) Integrated methods for construction three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 25:366-428.
5. Bockaert J and Pin JP (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO (Eur Mol Biol Organ) J 18:1723-1729.
6. Bordi F and Ugolini A (1999) Group I metabotropic glutamate receptors: implications for brain diseases. Prog Neurobiol 59:55-79.
7. Borhan B, Souto ML, Imai H, Shichida Y, and Nakanishi K (2000) Movement of retinal along the visual transduction path. Science (Wash DC) 288:2209-2212.
8. Breysse N, Baunez C, Spooren W, Gasparini F, and Amalric M (2002) Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J Neurosci 22:5669-5678.
9. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, and Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4:873-874.
10. Conn PJ and Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205-237.
11. De Blasi A, Conn PJ, Pin J, and Nicoletti F (2001) Molecular determinants of metabotropic glutamate receptor signaling. Trends Pharmacol Sci 22:114-120.
12. Farrens DL, Altenbach C, Yang K, Hubbell WL, and Khorana HG (1996) Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science (Wash DC) 274:768-770.
13. 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.
14. Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, et al. (1999) 2-Methyl-6-(phenylethynyl)pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493-1503.
15. Gerber PR (1998) Charge distribution from a simple molecular orbital type calculation and non-bonding interaction terms in the force field MAB. J Comput Aided Mol Des 12:37-51.
16. Gerber PR and Muller K (1995) MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry. J Comput Aided Mol Des 9:251-268.
17. 2+ receptors. Mol Pharmacol 55:642-648.
18. Hudson LJ, Bevan S, McNair K, Gentry C, Fox A, Kuhn R, and Winter J (2002) Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia. J Neurosci 22:2660-2668.
19. Joubert L, Claeysen S, Sebben M, Bessis AS, Clark RD, Martin RS, 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 277:25502-25511.
20. Knoflach F, Mutel V, Jolidon S, Kew JNC, Malherbe P, Vieira E, Wichmann J, and Kemp JA (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action and binding site. Proc Natl Acad Sci USA 98:13402-13407.
21. 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 (Lond) 407:971-977.
22. Litschig S, Gasparini F, Rueegg D, Stoehr N, Flor PJ, Vranesic I, Prezeau L, Pin JP, Thomsen C, and Kuhn R (1999) CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol Pharmacol 55:453-461.
23. Malherbe P, Knoflach F, Broger C, Ohresser S, Kratzeisen C, Adam G, Stadler H, Kemp JA, 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.
24. Malherbe P, Kratochwil N, Knoflach F, Zenner MT, Kew JN, Kratzeisen C, Maerki HP, Adam G, and Mutel V (2003) 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.
25. McGeehan AJ and Olive MF (2003) The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine but not other drugs of abuse. Synapse 47:240-242.
26. Mutel V (2002) Therapeutic potential of non-competitive, subtype-selective metabotropic glutamate receptor ligands. Expert Opin Ther Patents 12:1845-1852.
27. Pagano A, Ruegg D, Litschig S, Stoehr N, Stierlin C, Heinrich M, Floersheim P, Prezeau L, Carroll F, Pin JP, 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 275:33750-33758.
28. Palezewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, and Miyano M (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science (Wash DC) 289:739-745.
29. Parmentier ML, Prezeau L, Bockaert J, and Pin JP (2002) A model for the functioning of family 3 GPCRs. Trends Pharmacol Sci 23:268-274.
30. Pilc A, Klodzinska A, Branski P, Nowak G, Palucha A, Szewczyk B, Tatarczynska E, Chojnacka-Wojcik E, and Wieronska JM (2002) Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats. Neuropharmacology 43: 181-187.
31. Ponder JW and Richards FM (1987) Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes. J Mol Biol 193:775-791.
32. Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, and Sheardown MJ (1999) Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B, and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 128:13-20.
33. Romano C, Sesma MA, McDonald CT, O'Malley K, Van den Pol AN, and Olney JW (1995) Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 355:455-469.
34. Sakmar TP, Menon ST, Marin EP, and Awad ES (2002) Rhodopsin: insights from recent structural studies. Annu Rev Biophys Biomol Struct 31:443-484.
35. Sheikh SP, Zvyaga TA, Lichtarge O, Sakmar TP, and Bourne HR (1996) Rhodopsin activation blocked by metal-ion-binding sites linking transmembrane helices C and F. Nature (Lond) 383:347-350.
36. Shigemoto R, Nomura S, Ohishi H, Sugihara H, Nakanishi S, and Mizuno N (1993) Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Neurosci Lett 163:53-57.
37. Spooren WP, Gasparini F, Salt TE, and Kuhn R (2001) Novel allosteric antagonists shed light on mglu(5) receptors and CNS disorders. Trends Pharmacol Sci 22:331-337.
38. Spooren WP, Vassout A, Neijt HC, Kuhn R, Gasparini F, Roux S, Porsolt RD, and Gentsch C (2000) Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents. J Pharmacol Exp Ther 295:1267-1275.
39. Tatarezynska E, Klodzinska A, Chojnacka-Wojcik E, Palucha A, Gasparini F, Kuhn R, and Pilc A (2001) Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 132:1423-1430.
40. Teller DC, Okada T, Behnke CA, Palezewski K, and Stenkamp RE (2001) Adv in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochemistry 40:7761-7772.
41. Wieronska JM, Szewczyk B, Branski P, Palucha A, and Pilc A (2002) Antidepressant-like effect of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist in the olfactory bulbectomized rats. Amino Acids 23:213-216.