Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol- 4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications

Journal of Medicinal Chemistry

Volumn 49, Issue 3, 2006, Pages 1080-1100

  Iso, Yasuyoshi ^a   Grajkowska, Ewa ^b   Wroblewski, Jarda T ^b   Davis, Jared ^c   Goeders, Nicholas E ^c   Johnson, Kenneth M ^d   Sanker, Subramaniam ^e   Roth, Bryan L ^e   Tueckmantel, Werner ^f   Kozikowski, Alan P ^a  

^a UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^b GEORGETOWN UNIVERSITY MEDICAL CENTER   (United States)

^c LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^d University of Texas Medical Branch School of Medicine   (United States)

^e CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f Acenta Discovery Incorporated   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 METHYL 6 (PHENYLETHYNYL)PYRIDINE; 3 [(2 METHYL 4 THIAZOLYL)ETHYNYL] 5 VINYLPYRIDINE; 3 [(2 METHYL 4 THIAZOLYL)ETHYNYL]BENZONITRILE; 3 [(2 METHYL 4 THIAZOLYL)ETHYNYL]PYRIDINE; 4 CARBOXY 2 METHYLPHENYLGLYCINE; COCAINE; GLUTAMIC ACID; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ALLOSTERISM; ANIMAL CELL; ARTICLE; BINDING AFFINITY; DRUG ABUSE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELF ADMINISTRATION; DRUG STRUCTURE; DRUG SYNTHESIS; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ALLOSTERIC SITE; ANIMALS; CELL LINE; COCAINE; COCAINE-RELATED DISORDERS; CRICETINAE; CRICETULUS; HUMANS; LIGANDS; MALE; NARCOTICS; PYRIDINES; RADIOLIGAND ASSAY; RATS; RATS, WISTAR; RECEPTORS, METABOTROPIC GLUTAMATE; SELF ADMINISTRATION; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 32344445040     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050570f     Document Type: Article

References (53)

1. Pin, J. P.; Duvoisin, R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology 1995, 34, 1-26.
2. Brabet, I.; Mary, S.; Bockaert, J.; Pin, J. P. Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses. Neuropharmacology 1995, 34, 895-903.
3. Litschig, S.; Gasparini, F.; Rueegg, D.; Stoehr, N.; Flor, P. J.; Vranesic, I.; Prâezeau, L.; Pin, J. P.; Thomsen, C.; Kuhn, R. CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol. Pharmacol. 1999, 55, 453-461.
4. Gasparini, F.; Lingenhèohl, K.; Stoehr, N.; Flor, P. J.; Heinrich, M.; Vranesic, I.; Biollaz, M.; Allgeier, H.; Heckendorn, R.; Urwyler, S.; Varney, M. A.; Johnson, E. C.; Hess, S. D.; Rao, S. P.; Sacaan, A. I.; Santori, E. M.; Veliocelebi, G.; Kuhn, R. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 1999, 38, 1493-1503.
5. Cosford, N. D.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.; Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M. A. 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. 2003, 46, 204-206.
6. (a) Cosford, N. D.; Roppe, J.; Tehrani, L.; Schweiger, E. J.; Seiders, T. J.; Chaudary, A.; Rao, S.; Varney, M. A. [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor. Bioorg. Med. Chem. Lett. 2003, 13, 351-354.
7. (b) Huang, D.; Poon, S. F.; Chapman, D. F.; Chung, J.; Cramer, M.; Reger, T. S.; Roppe, J. R.; Tehrani, L.; Cosford, N. D.; Smith, N. D. 2-(2-[3-(pyridin-3-yloxy)-phenyl]-2H-tetrazol-5-yl) pyridine: a highly potent, orally active, metabotropic glutamate subtype 5 (mGlu5) receptor antagonist. Bioorg. Med. Chem. Lett. 2004, 14, 5473-5476.
8. (c) Poon, S. F.; Eastman, B. W.; Chapman, D. F.; Chung, J.; Cramer, M.; Holtz, G.; Cosford, N. D.; Smith, N. D. 3-[3-Fluoro-5-(5-pyridin-2-yl-2H- tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor antagonist. Bioorg. Med. Chem. Lett. 2004, 14, 5477-5480.
9. (d) Smith, N. D.; Poon, S. F.; Huang, D.; Green, M.; King, C.; Tehrani, L.; Roppe, J. R.; Chung, J.; Chapman, D. P.; Cramer, M.; Cosford, N. D. Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity. Bioorg. Med. Chem. Lett. 2004, 14, 5481-5484.
10. (e) Eastman, B.; Chen, C.; Smith, N. D.; Poon, S.; Chung, J.; Reyes-Manalo, G.; Cosford, N. D.; Munoz, B. Expedited SAR study of an mGluR5 antagonists: generation of a focused library using a solution-phase Suzuki coupling methodology. Bioorg. Med. Chem. Lett. 2004, 14, 5485-5488.
11. (f) Bonnefous, C.; Vernier, J. M.; Hutchinson, J. H.; Chung, J.; Reyes-Manalo, G.; Kamenecka, T. Dipyridyl amides: potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 1197-1200.
12. (g) Alagille, D.; Baldwin, R. M.; Roth, B. L.; Wroblewski, J. T.; Grajkowska, E.; Tamagnan, G. D. Synthesis and receptor assay of aromatic-ethynyl-aromatic derivatives with potent mGluR5 antagonist activity. Bioorg. Med. Chem. 2005, 13, 197-209.
13. (h) Alagille, D.; Baldwin, R. M.; Roth, B. L.; Wroblewski, J. T.; Grajkowska, E.; Tamagnan, G. D. Functionalization at position 3 of the phenyl ring of the potent mGluR5 noncompetitive antagonists MPEP. Bioorg. Med. Chem. Lett. 2005, 15, 945-949.
14. Gasparini, F.; Andres, H.; Flor, P. J.; Heinrich, M.; Inderbitzin, W.; Lingenhèohl, K.; Mèuller, H.; Munk, V. C.; Omilusik, K.; Stierlin, C.; Stoehr, N.; Vranesic, I.; Kuhn, R. [(3)H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5. Bioorg. Med. Chem. Lett. 2002, 12, 407-409.
15. (j) Roppe, J.; Smith, N. D.; Huang, D.; Tehrani, L.; Wang, B.; Anderson, J.; Brodkin, J.; Chung, J.; Jiang, X.; King, C.; Munoz, B.; Varney, M. A.; Prasit, P.; Cosford, N. D. Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity. J. Med. Chem. 2004, 47, 4645-4648.
16. (a) Pagano, A.; Ruegg, D.; Litschig, S.; Stoehr, N.; Stierlin, C.; Heinrich, M.; Floersheim, P.; Prezáeau, L.; Carroll, F.; Pin, J. P.; Cambria, A.; Vranesic, I.; Flor, P. J.; Gasparini, F.; Kuhn, R. 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. 2000, 275, 33750-33758.
17. (b) Malherbe, P.; Kratochwil, N.; Zenner, M. T.; Piussi, J.; Diener, C.; Kratzeisen, C.; Fischer, C.; Porter, R. H. Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine. Mol. Pharmacol. 2003, 64, 823-832.
18. (c) Goudet, C.; Gaven, F.; Kniazeff, J.; Vol, C.; Liu, J.; Cohen-Gonsaud, M.; Acher, F.; Prâezeau, L.; Pin, J. P. Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 378-383.
19. Chiamulera, C.; Epping-Jordan, M. P.; Zocchi, A.; Marcon, C.; Cottiny, C.; Tacconi, S.; Corsi, M.; Orzi, F.; Conquet, F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat. Neurosci. 2001, 4, 873-874.
20. Kim, J. H.; Vezina, P. Metabotropic glutamate receptors in the rat nucleus accumbens contribute to amphetamine-induced locomotion. J. Pharmacol. Exp. Ther. 1998, 284, 317-322.
21. Smith, J. A.; Mo, Q.; Guo, H.; Kunko, P. M.; Robinson, S. E. Cocaine increases extraneuronal levels of aspartate and glutamate in the nucleus accumbens. Brain. Res. 1995, 683, 264-269.
22. Pierce, R. C.; Bell, K.; Duffy, P.; Kalivas, P. W. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. J. Neurosci. 1996, 16, 1550-1560.
23. Tallaksen-Greene, S. J.; Kaatz, K. W.; Romano, C.; Albin, R. L. Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons. Brain. Res. 1998, 780, 210-217.
24. Choe, E. S.; Chung, K. T.; Mao, L.; Wang, J. Q. Amphetamine increases phosphorylation of extracellular signal-regulated kinase and transcription factors in the rat striatum via group I metabotropic glutamate receptors. Neuropsychopharmacology 2002, 27, 565-575.
25. McGeehan, A. J.; Olive, M. F. The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine but not other drugs of abuse. Synapse 2003, 47, 240-242.
26. Paterson, N. E.; Semenova, S.; Gasparini, F.; Markou, A. The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology (Berlin) 2003, 167, 257-264.
27. Popik, P.; Wrâobel, M. Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist. Neuropharmacology 2002, 43, 1210-1217.
28. (a) Spooren, W. P.; Gasparini, F.; Salt, T. E.; Kuhn, R. Novel allosteric antagonists shed light on mglu(5) receptors and CNS disorders. Trends Pharmacol. Sci. 2001, 22, 331-337.
29. (b) Gasparini, F.; Kuhn, R.; Pin, J. P. Allosteric modulators of group I metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr. Opin. Pharmacol. 2002, 2, 43-49.
30. Varney, M. A.; Cosford, N. D.; Jachec, C.; Rao, S. P.; Sacaan, A.; Lin, F. F.; Bleicher, L.; Santori, E. M.; Flor, P. J.; Allgeier, H.; Gasparini, F.; Kuhn, R.; Hess, S. D.; Veliocelebi, G.; Johnson, E. C. SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J. Pharmacol. Exp. Ther. 1999, 290, 170-181.
31. (a) O'Leary, D. M.; Movsesyan, V.; Vicini, S.; Faden, A. I. Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism. Br. J. Pharmacol. 2000, 131, 1429-1437.
32. (b) Movsesyan, V. A.; O'Leary, D. M.; Fan, L.; Bao, W.; Mullins, P. G.; Knoblach, S. M.; Faden, A. I. mGluR5 antagonists 2-methyl-6-(phenylethynyl)- pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors. J. Pharmacol. Exp. Ther. 2001, 296, 41-47.
33. Kim, D. K.; Kim, J.; Park, H. J. Synthesis and biological evaluation of novel 2-pyridinyl-[1,2,3]triazoles as inhibitors of transforming growth factor beta 1 type 1 receptor. Bioorg. Med. Chem. Lett. 2004, 14, 2401-2405.
34. Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. Alkyl nitrite-metal halide deamination reactions. 2. Substitutive deamination of arylamines by alkyl nitrites copper(II) halides. A direct and remarkably efficient conversion of arylamines to aryl halides. J. Org. Chem. 1977, 42, 2426-2431.
35. Rim, C.; Son, D. Y. Transmetalation as a route to novel styryllithium reagents. Org. Lett. 2003, 5, 3443-3445.
36. Kodomari, M.; Nagaoka, T.; Furusawa, Y. Convenient synthesis of aryl-substituted halo olefins from aromatic ketones and acetyl halides in the presence of silica gel-supported zinc halides. Tetrahedron Lett. 2001, 42, 3105-3107.
37. Trecourt, F.; Mallet, M.; Marsais, F.; Queguiner, G. Catalyzed metalation applied to 2-methoxypyridine. J. Org. Chem. 1988, 53, 1367-1371.
38. Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. Enantioselective total synthesis of the antitumor macrolide rhizoxin D. J. Org. Chem. 2003, 68, 4215-4234.
39. Barrish, J. C.; Singh, J.; Spergel, S. H.; Han, W. C.; Kisssick, T. P.; Kronenthal, D. R.; Mueller, R. H. Cupric bromide mediated oxidation of 4-carboxyoxazolines to the corresponding oxazoles. J. Org. Chem. 1993, 58, 4494-4496.
40. (a) Nicolaou, K. C.; Namoto, K.; Ritzâen, A.; Ulven, T.; Shoji, M.; Li, J.; D'Amico, G.; Liotta, D.; French, C. T.; Wartmann, M.; Altmann, K. H.; Giannakakou, P. Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues. J. Am. Chem. Soc. 2001, 123, 9313-9323.
41. (b) Grandjean, D. P., P.; Chuche, J. An improved procedure for aldehyde-to-alkyne homologation via 1,1-dibromoalkenes; synthesis of 1-bromoalkynes. Tetrahedron Lett. 1994, 35, 3529-3530.
42. Iso, Y.; Kozikowski, A. P. Synthesis of 4-arylethynyl-2-methyloxazole derivatives as mGluR5 antagonists for use in drug abuse. Synthesis In press.
43. (a) Harrison, A. A.; Gasparini, F.; Markou, A. Nicotine potentiation of brain stimulation reward reversed by DH beta E and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats. Psychopharmacology (Berlin) 2002, 160, 56-66.
44. (b) Kenny, P. J.; Boutrel, B.; Gasparini, F.; Koob, G. F.; Markou, A. Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology (Berlin) 2005, 179, 247-254.
45. Anderson, J. J.; Bradbury, M. J.; Giracello, D. R.; Chapman, D. F.; Holtz, G.; Roppe, J.; King, C.; Cosford, N. D.; Varney, M. A. In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine). Eur. J. Pharmacol. 2003, 473, 35-40.
46. Varty, G. B.; Grilli, M.; Forlani, A.; Fredduzzi, S.; Grzelak, M. E.; Guthrie, D. H.; Hodgson, R. A.; Lu, S. X.; Nicolussi, E.; Pond, A. J.; Parker, E. M.; Hunter, J. C.; Higgins, G. A.; Reggiani, A.; Bertorelli, R. The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles. Psychopharmacology (Berlin) 2005, 179, 207-217.
47. Kozikowski, A. P.; Steensma, D.; Araldi, G. L.; Tèuckmantel, W.; Wang, S.; Pshenichkin, S.; Surina, E.; Wroblewski, J. T. Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2, 5-dicarboxylic acid-I, a potent mGluR agonist. J. Med. Chem. 1998, 41, 1641-1650.
48. (a) Koob, G. F.; Goeders, N. E. Neuroanatomical substrates of drug self-administration. In: Liebman, J. M.; Cooper, S. J., editors, Oxford Reviews in Psychopharmacology, Vol. 1., Neuropharmacological Basis of Reward. London: Oxford University Press: 1989; 214-263.
49. (b) Goeders, N. E.; Peltier, R. L.; Guerin, G. F. Ketoconazole reduces low dose cocaine self-administration in rats. Drug Alcohol Depend. 1998, 53, 67-77.
50. Goeders, N. E.; Clampitt, D. M. Potential role for the hypothalamo-pituitary-adrenal axis in the conditioned reinforcer-induced reinstatement of extinguished cocaine seeking in rats. Psychopharmacology (Berlin) 2002, 161, 222-232.
51. Mukhopadhyaya, J. K.; Kozikowski, A. P.; Grajkowska, E.; Pshenichkin, S.; Wroblewski, J. T. Synthesis of N(1)-substituted analogues of (2R,4R)-4-amino-pyrrolidine-2,4-dicarboxylic acid as agonists, partial agonists, and antagonists of group II metabotropic glutamate receptors. Bioorg. Med. Chem. Lett. 2001, 11, 1919-1924.
52. Wroblewska, B.; Wroblewski, J. T.; Pshenichkin, S.; Surin, A.; Sullivan, S. E.; Neale, J. H. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 1997, 69, 174-181.
53. Raulli, R.; Danysz, W.; Wroblewski, J. T. Pretreatment of cerebellar granule cells with concanavalin A potentiates quisqualate-stimulated phosphoinositide hydrolysis. J. Neurochem. 1991, 56, 2116-2124.