MTEP

MTEP

Systematic (IUPAC) name
3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine
Identifiers
CAS Number	329205-68-7
PubChem	CID 9794218
IUPHAR/BPS	3336
ChemSpider	7969985
Chemical data
Formula	C11H8N2S
Molar mass	200.260 g/mol
SMILES CC1=NC(=CS1)C#CC2=CN=CC=C2
InChI InChI=1S/C11H8N2S/c1-9-13-11(8-14-9)5-4-10-3-2-6-12-7-10/h2-3,6-8H,1H3 Key:NRBNGHCYDWUVLC-UHFFFAOYSA-N
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3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP,^[1] MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.^[2][3]

MTEP is both more potent and more selective than MPEP as a mGluR5 antagonist,^[4] and produces similar neuroprotective,^[5][6][7] antidepressant,^{[8][9][10][11]} analgesic,^[12][13] and anxiolytic effects but with either similar or higher efficacy depending on the test used.^{[14][15][16][17]}

MTEP also has similar efficacy to MPEP in reducing the symptoms of morphine withdrawal,^[18][19][20] and has anti-addictive effects in a variety of animal models, both reducing ethanol self-administration,^{[21][22][23][24]} and also decreasing the addictive effects of nicotine, cocaine and methamphetamine.^{[25][26][27][28][29]}

References

1. Cosford ND, Tehrani L, Roppe J, et al. (January 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 (2): 204–6. doi:10.1021/jm025570j. PMID 12519057.
2. Iso Y, Grajkowska E, Wroblewski JT, et al. (February 2006). "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". J. Med. Chem. 49 (3): 1080–100. doi:10.1021/jm050570f. PMID 16451073.
3. Kulkarni SS, Newman AH (June 2007). "Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists". Bioorg. Med. Chem. Lett. 17 (11): 2987–91. doi:10.1016/j.bmcl.2007.03.066. PMC 1973162. PMID 17446071.
4. Lea, P. M.; Faden, A. I. (2006). "Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP". CNS Drug Reviews 12 (2): 149–166. doi:10.1111/j.1527-3458.2006.00149.x. PMID 16958988.
5. Lea, P. M.; Movsesyan, V. A.; Faden, A. I. (2009). "Neuroprotective activity of the mGluR5 antagonists MPEP and MTEP against acute excitotoxicity differs and does not reflect actions at mGluR5 receptors". British Journal of Pharmacology 145 (4): 527–534. doi:10.1038/sj.bjp.0706219. PMC 1576169. PMID 15821750.
6. Domin, H.; Kajta, M.; Smiałowska, M. (2006). "Neuroprotective effects of MTEP, a selective mGluR5 antagonists and neuropeptide Y on the kainate-induced toxicity in primary neuronal cultures". Pharmacological reports : PR 58 (6): 846–858. PMID 17220542.
7. Szydlowska, K.; Kaminska, B.; Baude, A.; Parsons, C. G.; Danysz, W. (2007). "Neuroprotective activity of selective mGlu1 and mGlu5 antagonists in vitro and in vivo". European Journal of Pharmacology 554 (1): 18–29. doi:10.1016/j.ejphar.2006.09.061. PMID 17109843.
8. Pałucha, A.; Brański, P.; Szewczyk, B.; Wierońska, J. M.; Kłak, K.; Pilc, A. (2005). "Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist". Pharmacology Biochemistry and Behavior 81 (4): 901. doi:10.1016/j.pbb.2005.06.015.
9. Molina-Hernández, M.; Tellez-Alcántara, N. P.; Pérez-García, J. N.; Olivera-Lopez, J. I. N.; Jaramillo, M. T. (2006). "Antidepressant-like and anxiolytic-like actions of the mGlu5 receptor antagonist MTEP, microinjected into lateral septal nuclei of male Wistar rats". Progress in Neuro-Psychopharmacology and Biological Psychiatry 30 (6): 1129–1135. doi:10.1016/j.pnpbp.2006.04.022. PMID 16759778.
10. Li, X.; Need, A. B.; Baez, M.; Witkin, J. M. (2006). "Metabotropic Glutamate 5 Receptor Antagonism is Associated with Antidepressant-Like Effects in Mice". Journal of Pharmacology and Experimental Therapeutics 319 (1): 254–259. doi:10.1124/jpet.106.103143. PMID 16803860.
11. Belozertseva, I.; Kos, T.; Popik, P.; Danysz, W.; Bespalov, A. (2007). "Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests". European Neuropsychopharmacology 17 (3): 172–179. doi:10.1016/j.euroneuro.2006.03.002. PMID 16630709.
12. Zhu, C. Z.; Wilson, S. G.; Mikusa, J. P.; Wismer, C. T.; Gauvin, D. M.; Lynch Jj, J. J.; Wade, C. L.; Decker, M. W.; Honore, P. (2004). "Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities". European Journal of Pharmacology 506 (2): 107–118. doi:10.1016/j.ejphar.2004.11.005. PMID 15588730.
13. 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. (2005). "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 179 (1): 207–217. doi:10.1007/s00213-005-2143-4. PMID 15682298.
14. Klodzinska, A.; Tatarczyńska, E.; Chojnacka-Wójcik, E.; Nowak, G.; Cosford, N. D. P.; Pilc, A. (2004). "Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABAA signaling". Neuropharmacology 47 (3): 342–350. doi:10.1016/j.neuropharm.2004.04.013. PMID 15275823.
15. Busse, C. S.; Brodkin, J.; Tattersall, D.; Anderson, J. J.; Warren, N.; Tehrani, L.; Bristow, L. J.; Varney, M. A.; Cosford, N. D. (2004). "The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-\(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety". Neuropsychopharmacology 29 (11): 1971–1979. doi:10.1038/sj.npp.1300540. PMID 15305166.
16. Pietraszek, M. G.; Sukhanov, I.; MacIejak, P.; Szyndler, J.; Gravius, A.; Wisłowska, A.; Płaźnik, A.; Bespalov, A. Y.; Danysz, W. (2005). "Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats". European Journal of Pharmacology 514 (1): 25–34. doi:10.1016/j.ejphar.2005.03.028. PMID 15878321.
17. Stachowicz, K.; Gołembiowska, K.; Sowa, M.; Nowak, G.; Chojnacka-Wójcik, E.; Pilc, A. (2007). "Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent". Neuropharmacology 53 (6): 741–748. doi:10.1016/j.neuropharm.2007.08.002. PMID 17870136.
18. Pałucha A, Brański P, Pilc A (2004). "Selective mGlu5 receptor antagonist MTEP attenuates naloxone-induced morphine with-drawal symptoms" (PDF). Pol J Pharmacol 56 (6): 863–6. PMID 15662102.
19. Rasmussen K, Martin H, Berger JE, Seager MA (February 2005). "The mGlu5 receptor antagonists MPEP and MTEP attenuate behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons in rats". Neuropharmacology 48 (2): 173–80. doi:10.1016/j.neuropharm.2004.09.010. PMID 15695156.
20. Kotlinska J, Bochenski M (March 2007). "Comparison of the effects of mGluR1 and mGluR5 antagonists on the expression of behavioral sensitization to the locomotor effect of morphine and the morphine withdrawal jumping in mice". Eur. J. Pharmacol. 558 (1-3): 113–8. doi:10.1016/j.ejphar.2006.11.067. PMID 17222405.
21. Cowen MS, Djouma E, Lawrence AJ (November 2005). "The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems". J. Pharmacol. Exp. Ther. 315 (2): 590–600. doi:10.1124/jpet.105.090449. PMID 16014750.
22. Cowen MS, Krstew E, Lawrence AJ (January 2007). "Assessing appetitive and consummatory phases of ethanol self-administration in C57BL/6J mice under operant conditions: regulation by mGlu5 receptor antagonism". Psychopharmacology (Berl.) 190 (1): 21–9. doi:10.1007/s00213-006-0583-0. PMID 17096086.
23. Adams CL, Cowen MS, Short JL, Lawrence AJ (March 2008). "Combined antagonism of glutamate mGlu5 and adenosine A2A receptors interact to regulate alcohol-seeking in rats". Int. J. Neuropsychopharmacol. 11 (2): 229–41. doi:10.1017/S1461145707007845. PMID 17517168.
24. Kotlinska J, Bochenski M (November 2008). "The influence of various glutamate receptors antagonists on anxiety-like effect of ethanol withdrawal in a plus-maze test in rats". Eur. J. Pharmacol. 598 (1-3): 57–63. doi:10.1016/j.ejphar.2008.09.026. PMID 18838071.
25. Dravolina OA, Danysz W, Bespalov AY (September 2006). "Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats". Psychopharmacology (Berl.) 187 (4): 397–404. doi:10.1007/s00213-006-0440-1. PMID 16896963.
26. Palmatier MI, Liu X, Donny EC, Caggiula AR, Sved AF (August 2008). "Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine". Neuropsychopharmacology 33 (9): 2139–47. doi:10.1038/sj.npp.1301623. PMC 2812904. PMID 18046312.
27. Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF (March 2009). "mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats". Neuropsychopharmacology 34 (4): 820–33. doi:10.1038/npp.2008.140. PMC 2669746. PMID 18800068.
28. Osborne MP, Olive MF (October 2008). "A role for mGluR5 receptors in intravenous methamphetamine self-administration". Ann. N. Y. Acad. Sci. 1139: 206–11. doi:10.1196/annals.1432.034. PMID 18991866.
29. Martin-Fardon R, Baptista MA, Dayas CV, Weiss F (June 2009). "Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer". J. Pharmacol. Exp. Ther. 329 (3): 1084–90. doi:10.1124/jpet.109.151357. PMC 2683783. PMID 19258516.