2-Methyl-6-(phenylethynyl)pyridine

2-Methyl-6-(phenylethynyl)pyridine

Systematic (IUPAC) name
2-Methyl-6-(phenylethynyl)pyridine
Identifiers
CAS Number	96206-92-7
PubChem	CID 3025961
IUPHAR/BPS	1426
ChemSpider	7970355
UNII	7VC0YVI27Y
Chemical data
Formula	C14H11N
Molar mass	193.243 g/mol
SMILES CC1=CC=CC(=N1)C#CC2=CC=CC=C2
InChI InChI=1S/C14H11N.ClH/c1-12-6-5-9-14(15-12)11-10-13-7-3-2-4-8-13;/h2-9H,1H3;1H Key:PKDHDJBNEKXCBI-UHFFFAOYSA-N
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2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical company Novartis in the late 1990s.^[1] It was found to produce neuroprotective effects following acute brain injury in animal studies, although it was unclear whether these results were purely from mGluR5 blockade as it also acts as a weak NMDA antagonist,^[2][3] and as a positive allosteric modulator of another subtype mGlu4,^[4] and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons.^[5] It was also shown to produce antidepressant^[6][7][8] and anxiolytic effects in animals,^[9][10][11] and to reduce the effects of morphine withdrawal,^[12] most likely due to direct interaction between mGluR5 and the μ-opioid receptor.^[13]

The main significance of MPEP has been as a lead compound to develop more potent and selective mGluR5 antagonists such as MTEP,^[14] but research using MPEP itself continues, and recently it was shown to reduce self-administration of nicotine,^[15][16] cocaine,^[17][18] ketamine and heroin in animals,^[19] possibly through an MPEP-induced potentiation of the rewarding effect of the self-administered drug,^[20] and MPEP was also shown to possess weak reinforcing effects by itself.^[21]

References

1. Micheli, F (2000). "Methylphenylethynylpyridine (MPEP) Novartis". Current opinion in investigational drugs (London, England : 2000) 1 (3): 355–9. PMID 11249719.
2. O'Leary, DM; Movsesyan, V; Vicini, S; Faden, AI (2000). "Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism". British Journal of Pharmacology 131 (7): 1429–37. doi:10.1038/sj.bjp.0703715. PMC 1572472. PMID 11090117.
3. Movsesyan, VA; O'Leary, DM; Fan, L; Bao, W; Mullins, PG; Knoblach, SM; Faden, AI (2001). "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". The Journal of Pharmacology and Experimental Therapeutics 296 (1): 41–7. PMID 11123360.
4. Mathiesen, JM; Svendsen, N; Bräuner-Osborne, H; Thomsen, C; Ramirez, MT (2003). "Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP". British Journal of Pharmacology 138 (6): 1026–30. doi:10.1038/sj.bjp.0705159. PMC 1573757. PMID 12684257.
5. Pisani, A; Gubellini, P; Bonsi, P; Conquet, F; Picconi, B; Centonze, D; Bernardi, G; Calabresi, P (2001). "Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons". Neuroscience 106 (3): 579–87. doi:10.1016/S0306-4522(01)00297-4. PMID 11591458.
6. Li, X; Need, AB; Baez, M; Witkin, JM (2006). "Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice". The Journal of Pharmacology and Experimental Therapeutics 319 (1): 254–9. doi:10.1124/jpet.106.103143. PMID 16803860.
7. Tatarczyńska, E; Klodzińska, A; Chojnacka-Wójcik, E; Palucha, A; Gasparini, F; Kuhn, R; Pilc, A (2001). "Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist". British Journal of Pharmacology 132 (7): 1423–30. doi:10.1038/sj.bjp.0703923. PMC 1572682. PMID 11264235.
8. Pilc, A; Kłodzińska, A; Brański, P; Nowak, G; Pałucha, A; Szewczyk, B; Tatarczyńska, E; Chojnacka-Wójcik, E; Wierońska, JM (2002). "Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats". Neuropharmacology 43 (2): 181–7. doi:10.1016/S0028-3908(02)00082-5. PMID 12213272.
9. Kłodzińska, A; Tatarczyńska, E; Chojnacka-Wójcik, E; Pilc, A (2000). "Anxiolytic-like effects of group I metabotropic glutamate antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in rats". Polish journal of pharmacology 52 (6): 463–6. PMID 11334240.
10. Ballard, TM; Woolley, ML; Prinssen, E; Huwyler, J; Porter, R; Spooren, W (2005). "The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison". Psychopharmacology 179 (1): 218–29. doi:10.1007/s00213-005-2211-9. PMID 15739074.
11. 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.
12. Rasmussen, K; Martin, H; Berger, JE; Seager, MA (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.
13. Schröder, H; Wu, DF; Seifert, A; Rankovic, M; Schulz, S; Höllt, V; Koch, T (2009). "Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the micro-opioid receptor". Neuropharmacology 56 (4): 768–78. doi:10.1016/j.neuropharm.2008.12.010. PMID 19162047.
14. Lea Pm, 4th; Faden, AI (2006). "Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP". CNS Drug Reviews 12 (2): 149–66. doi:10.1111/j.1527-3458.2006.00149.x. PMID 16958988.
15. Paterson, NE; Semenova, S; Gasparini, F; Markou, A (2003). "The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice". Psychopharmacology 167 (3): 257–64. doi:10.1007/s00213-003-1432-z. PMID 12682710.
16. Bespalov, AY; Dravolina, OA; Sukhanov, I; Zakharova, E; Blokhina, E; Zvartau, E; Danysz, W; Van Heeke, G; Markou, A (2005). "Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats". Neuropharmacology. 49 Suppl 1: 167–78. doi:10.1016/j.neuropharm.2005.06.007. PMID 16023685.
17. Tessari, M; Pilla, M; Andreoli, M; Hutcheson, DM; Heidbreder, CA (2004). "Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking". European Journal of Pharmacology 499 (1–2): 121–33. doi:10.1016/j.ejphar.2004.07.056. PMID 15363959.
18. Paterson, NE; Markou, A (2005). "The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats". Psychopharmacology 179 (1): 255–61. doi:10.1007/s00213-004-2070-9. PMID 15619120.
19. Van Der Kam, EL; De Vry, J; Tzschentke, TM (2007). "Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat". Behavioural Pharmacology 18 (8): 717–24. doi:10.1097/FBP.0b013e3282f18d58. PMID 17989509.
20. Van Der Kam, EL; De Vry, J; Tzschentke, TM (2009). "2-Methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward as assessed by acquisition, extinction, and reinstatement of conditioned place preference in the rat". European Journal of Pharmacology 606 (1–3): 94–101. doi:10.1016/j.ejphar.2008.12.042. PMID 19210976.
21. Van Der Kam, EL; De Vry, J; Tzschentke, TM (2009). "The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intravenous self-administration and induces conditioned place preference in the rat". European Journal of Pharmacology 607 (1–3): 114–20. doi:10.1016/j.ejphar.2009.01.049. PMID 19326478.