MTEP explained

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]

See also

Notes and References

  1. Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith ND, Anderson J, Bristow L, Brodkin J, Jiang X, McDonald I, Rao S, Washburn M, Varney MA . 6 . 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity . Journal of Medicinal Chemistry . 46 . 2 . 204–206 . January 2003 . 12519057 . 10.1021/jm025570j .
  2. Iso Y, Grajkowska E, Wroblewski JT, Davis J, Goeders NE, Johnson KM, Sanker S, Roth BL, Tueckmantel W, Kozikowski AP . 6 . 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 . 49 . 3 . 1080–1100 . February 2006 . 16451073 . 10.1021/jm050570f .
  3. Kulkarni SS, Newman AH . Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists . Bioorganic & Medicinal Chemistry Letters . 17 . 11 . 2987–2991 . June 2007 . 17446071 . 1973162 . 10.1016/j.bmcl.2007.03.066 .
  4. Lea PM, Faden AI . Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP . CNS Drug Reviews . 12 . 2 . 149–166 . 2006 . 16958988 . 6494124 . 10.1111/j.1527-3458.2006.00149.x .
  5. Lea PM, Movsesyan VA, Faden AI . 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 . June 2005 . 15821750 . 1576169 . 10.1038/sj.bjp.0706219 .
  6. Domin H, Kajta M, Smiałowska M . Neuroprotective effects of MTEP, a selective mGluR5 antagonists and neuropeptide Y on the kainate-induced toxicity in primary neuronal cultures . Pharmacological Reports . 58 . 6 . 846–858 . 2006 . 17220542 .
  7. Szydlowska K, Kaminska B, Baude A, Parsons CG, Danysz W . Neuroprotective activity of selective mGlu1 and mGlu5 antagonists in vitro and in vivo . European Journal of Pharmacology . 554 . 1 . 18–29 . January 2007 . 17109843 . 10.1016/j.ejphar.2006.09.061 .
  8. Pałucha A, Brański P, Szewczyk B, Wierońska JM, Kłak K, Pilc A . Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist . Pharmacology, Biochemistry, and Behavior . 81 . 4 . 901–906 . August 2005 . 16040106 . 10.1016/j.pbb.2005.06.015 . 42920507 .
  9. Molina-Hernández M, Tellez-Alcántara NP, Pérez-García J, Olivera-Lopez JI, Jaramillo MT . 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 & Biological Psychiatry . 30 . 6 . 1129–1135 . August 2006 . 16759778 . 10.1016/j.pnpbp.2006.04.022 . 45937198 .
  10. Li X, Need AB, Baez M, Witkin JM . Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice . The Journal of Pharmacology and Experimental Therapeutics . 319 . 1 . 254–259 . October 2006 . 16803860 . 10.1124/jpet.106.103143 . 14632318 .
  11. Belozertseva IV, Kos T, Popik P, Danysz W, Bespalov AY . 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 . February 2007 . 16630709 . 10.1016/j.euroneuro.2006.03.002 . 2420850 .
  12. Zhu CZ, Wilson SG, Mikusa JP, Wismer CT, Gauvin DM, Lynch JJ, Wade CL, Decker MW, Honore P . 6 . Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities . European Journal of Pharmacology . 506 . 2 . 107–118 . December 2004 . 15588730 . 10.1016/j.ejphar.2004.11.005 .
  13. Varty GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, Hodgson RA, Lu SX, Nicolussi E, Pond AJ, Parker EM, Hunter JC, Higgins GA, Reggiani A, Bertorelli R . 6 . 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 . April 2005 . 15682298 . 10.1007/s00213-005-2143-4 . 21807900 .
  14. Klodzinska A, Tatarczyńska E, Chojnacka-Wójcik E, Nowak G, Cosford ND, Pilc A . Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling . Neuropharmacology . 47 . 3 . 342–350 . September 2004 . 15275823 . 10.1016/j.neuropharm.2004.04.013 . 54432014 .
  15. Busse CS, Brodkin J, Tattersall D, Anderson JJ, Warren N, Tehrani L, Bristow LJ, Varney MA, Cosford ND . 6 . 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 . November 2004 . 15305166 . 10.1038/sj.npp.1300540 . free .
  16. Pietraszek M, Sukhanov I, Maciejak P, Szyndler J, Gravius A, Wisłowska A, Płaźnik A, Bespalov AY, Danysz W . 6 . Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats . European Journal of Pharmacology . 514 . 1 . 25–34 . May 2005 . 15878321 . 10.1016/j.ejphar.2005.03.028 .
  17. Stachowicz K, Gołembiowska K, Sowa M, Nowak G, Chojnacka-Wójcik E, Pilc A . Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent . Neuropharmacology . 53 . 6 . 741–748 . November 2007 . 17870136 . 10.1016/j.neuropharm.2007.08.002 . 24833690 .
  18. Pałucha A, Brański P, Pilc A . Selective mGlu5 receptor antagonist MTEP attenuates naloxone-induced morphine withdrawal symptoms . Polish Journal of Pharmacology . 56 . 6 . 863–866 . 2004 . 15662102 .
  19. Rasmussen K, Martin H, Berger JE, Seager MA . 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 . 173–180 . February 2005 . 15695156 . 10.1016/j.neuropharm.2004.09.010 . 13552709 .
  20. Kotlinska J, Bochenski M . 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 . European Journal of Pharmacology . 558 . 1–3 . 113–118 . March 2007 . 17222405 . 10.1016/j.ejphar.2006.11.067 .
  21. Cowen MS, Djouma E, Lawrence AJ . 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 . The Journal of Pharmacology and Experimental Therapeutics . 315 . 2 . 590–600 . November 2005 . 16014750 . 10.1124/jpet.105.090449 . 11501029 .
  22. Cowen MS, Krstew E, Lawrence AJ . Assessing appetitive and consummatory phases of ethanol self-administration in C57BL/6J mice under operant conditions: regulation by mGlu5 receptor antagonism . Psychopharmacology . 190 . 1 . 21–29 . January 2007 . 17096086 . 10.1007/s00213-006-0583-0 . 19977179 .
  23. Adams CL, Cowen MS, Short JL, Lawrence AJ . Combined antagonism of glutamate mGlu5 and adenosine A2A receptors interact to regulate alcohol-seeking in rats . The International Journal of Neuropsychopharmacology . 11 . 2 . 229–241 . March 2008 . 17517168 . 10.1017/S1461145707007845 . free . 11343/32923 . free .
  24. Kotlinska J, Bochenski M . The influence of various glutamate receptors antagonists on anxiety-like effect of ethanol withdrawal in a plus-maze test in rats . European Journal of Pharmacology . 598 . 1–3 . 57–63 . November 2008 . 18838071 . 10.1016/j.ejphar.2008.09.026 .
  25. Dravolina OA, Danysz W, Bespalov AY . Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats . Psychopharmacology . 187 . 4 . 397–404 . September 2006 . 16896963 . 10.1007/s00213-006-0440-1 . 21231365 .
  26. Palmatier MI, Liu X, Donny EC, Caggiula AR, Sved AF . Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine . Neuropsychopharmacology . 33 . 9 . 2139–2147 . August 2008 . 18046312 . 2812904 . 10.1038/sj.npp.1301623 .
  27. Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF . mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats . Neuropsychopharmacology . 34 . 4 . 820–833 . March 2009 . 18800068 . 2669746 . 10.1038/npp.2008.140 .
  28. Osborne MP, Olive MF . A role for mGluR5 receptors in intravenous methamphetamine self-administration . Annals of the New York Academy of Sciences . 1139 . 1 . 206–211 . October 2008 . 18991866 . 10.1196/annals.1432.034 . 207012906 . 2008NYASA1139..206O .
  29. Martin-Fardon R, Baptista MA, Dayas CV, Weiss F . 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 . The Journal of Pharmacology and Experimental Therapeutics . 329 . 3 . 1084–1090 . June 2009 . 19258516 . 2683783 . 10.1124/jpet.109.151357 .

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