MTEP

MTEP

MTEP
Skeletal formula
Space-filling model
Systematic (IUPAC) name
3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine
Clinical data
Legal status
?
Identifiers
CAS number  YesY
ATC code ?
PubChem
ChemSpider  N
Chemical data
Formula C11H8N2S 
Mol. mass 200.260 g/mol
 N   

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.  
  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.  
  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.  
  4. ^ Lea, P. M.; Faden, A. I. (2006). "Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP". CNS Drug Reviews 12 (2): 149–166.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  18. ^ Pałucha A, Brański P, Pilc A (2004). "Selective mGlu5 receptor antagonist MTEP attenuates naloxone-induced morphine with-drawal symptoms". Pol J Pharmacol 56 (6): 863–6.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.