2-Methyl-6-(phenylethynyl)pyridine

2-Methyl-6-(phenylethynyl)pyridine
Identifiers
IUPAC name
  • 2-Methyl-6-(phenylethynyl)pyridine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H11N
Molar mass193.249 g·mol−1
3D model (JSmol)
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 checkY
  • Key:PKDHDJBNEKXCBI-UHFFFAOYSA-N checkY
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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]

See also

References

  1. ↑ Micheli F (November 2000). "Methylphenylethynylpyridine (MPEP) Novartis". Current Opinion in Investigational Drugs. 1 (3): 355–9. PMID 11249719.
  2. ↑ O'Leary DM, Movsesyan V, Vicini S, Faden AI (December 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 (January 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 (March 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, et al. (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 (October 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 (April 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, et al. (August 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 (April 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 GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, et al. (April 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): 207–17. doi:10.1007/s00213-005-2143-4. PMID 15682298.
  12. ↑ 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.
  13. ↑ Schröder H, Wu DF, Seifert A, Rankovic M, Schulz S, Höllt V, Koch T (March 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, 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. PMC 6494124. PMID 16958988.
  15. ↑ Paterson NE, Semenova S, Gasparini F, Markou A (May 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, et al. (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 (September 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 (April 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 (December 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 (March 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 (April 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.
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