2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selectiveantagonist for themetabotropic glutamate receptor subtypemGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical companyNovartis in the late 1990s.[1] It was found to produceneuroprotective 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 weakNMDA antagonist,[2][3] and as a positive allosteric modulator of another subtypemGlu4,[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 produceantidepressant[6][7][8] andanxiolytic 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 asMTEP,[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]
^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.PMID11123360.
^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.PMID11591458.S2CID38753726.
^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.PMID16803860.S2CID14632318.
^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.PMID12213272.S2CID23177632.
^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.PMID11334240.
^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.PMID15739074.S2CID25136496.
^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.PMID15682298.S2CID21807900.
^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.PMID15695156.S2CID13552709.
^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.PMID19162047.S2CID41530896.
^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.PMID12682710.S2CID40627145.
^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.PMID16023685.S2CID37283433.
^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.PMID15363959.
^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.PMID15619120.S2CID24096619.
^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.PMID17989509.S2CID24990842.
^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.PMID19210976.
^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.PMID19326478.
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