|Systematic (IUPAC) name|
|Mol. mass||193.243 g/mol|
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. 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, and as a positive allosteric modulator of another subtype mGlu4, and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons. It was also shown to produce antidepressant and anxiolytic effects in animals, and to reduce the effects of morphine withdrawal, most likely due to direct interaction between mGluR5 and the μ-opioid receptor.
The main significance of MPEP has been as a lead compound to develop more potent and selective mGluR5 antagonists such as MTEP, but research using MPEP itself continues, and recently it was shown to reduce self-administration of nicotine, cocaine, ketamine and heroin in animals, possibly through an MPEP-induced potentiation of the rewarding effect of the self-administered drug, and MPEP was also shown to possess weak reinforcing effects by itself.
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- 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".
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Lea Pm, 4th; Faden, AI (2006). "Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP". CNS Drug Reviews 12 (2): 149–66.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.