2-Methyl-6-(phenylethynyl)pyridine

{{short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 477214380

| IUPAC_name = 2-Methyl-6-(phenylethynyl)pyridine

| image = Methylphenylethynylpyridine.svg

| width = 200

| tradename =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US =

| legal_status =

| routes_of_administration =

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 96206-92-7

| ATC_prefix =

| ATC_suffix =

| PubChem = 3025961

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 7VC0YVI27Y

| IUPHAR_ligand = 1426

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank =

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 7970355

| C=14 | H=11 | N=1

| smiles = CC1=CC=CC(=N1)C#CC2=CC=CC=C2

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C14H11N.ClH/c1-12-6-5-9-14(15-12)11-10-13-7-3-2-4-8-13;/h2-9H,1H3;1H

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = PKDHDJBNEKXCBI-UHFFFAOYSA-N

}}

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.{{cite journal | vauthors = Micheli F | title = Methylphenylethynylpyridine (MPEP) Novartis | journal = Current Opinion in Investigational Drugs | volume = 1 | issue = 3 | pages = 355–9 | date = November 2000 | pmid = 11249719 }} 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,{{cite journal | vauthors = O'Leary DM, Movsesyan V, Vicini S, Faden AI | title = Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism | journal = British Journal of Pharmacology | volume = 131 | issue = 7 | pages = 1429–37 | date = December 2000 | pmid = 11090117 | pmc = 1572472 | doi = 10.1038/sj.bjp.0703715 }}{{cite journal | vauthors = Movsesyan VA, O'Leary DM, Fan L, Bao W, Mullins PG, Knoblach SM, Faden AI | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 296 | issue = 1 | pages = 41–7 | date = January 2001 | pmid = 11123360 }} and as a positive allosteric modulator of another subtype mGlu4,{{cite journal | vauthors = Mathiesen JM, Svendsen N, Bräuner-Osborne H, Thomsen C, Ramirez MT | title = Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP | journal = British Journal of Pharmacology | volume = 138 | issue = 6 | pages = 1026–30 | date = March 2003 | pmid = 12684257 | pmc = 1573757 | doi = 10.1038/sj.bjp.0705159 }} and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons.{{cite journal | vauthors = Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, Bernardi G, Calabresi P | display-authors = 6 | title = Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons | journal = Neuroscience | volume = 106 | issue = 3 | pages = 579–87 | year = 2001 | pmid = 11591458 | doi = 10.1016/S0306-4522(01)00297-4 | s2cid = 38753726 }} It was also shown to produce antidepressant{{cite journal | vauthors = Li X, Need AB, Baez M, Witkin JM | title = Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 319 | issue = 1 | pages = 254–9 | date = October 2006 | pmid = 16803860 | doi = 10.1124/jpet.106.103143 | s2cid = 14632318 }}{{cite journal | vauthors = Tatarczyńska E, Klodzińska A, Chojnacka-Wójcik E, Palucha A, Gasparini F, Kuhn R, Pilc A | title = Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist | journal = British Journal of Pharmacology | volume = 132 | issue = 7 | pages = 1423–30 | date = April 2001 | pmid = 11264235 | pmc = 1572682 | doi = 10.1038/sj.bjp.0703923 }}{{cite journal | vauthors = Pilc A, Kłodzińska A, Brański P, Nowak G, Pałucha A, Szewczyk B, Tatarczyńska E, Chojnacka-Wójcik E, Wierońska JM | display-authors = 6 | title = Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats | journal = Neuropharmacology | volume = 43 | issue = 2 | pages = 181–7 | date = August 2002 | pmid = 12213272 | doi = 10.1016/S0028-3908(02)00082-5 | s2cid = 23177632 }} and anxiolytic effects in animals,{{cite journal | vauthors = Kłodzińska A, Tatarczyńska E, Chojnacka-Wójcik E, Pilc A | title = Anxiolytic-like effects of group I metabotropic glutamate antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in rats | journal = Polish Journal of Pharmacology | volume = 52 | issue = 6 | pages = 463–6 | year = 2000 | pmid = 11334240 }}{{cite journal | vauthors = Ballard TM, Woolley ML, Prinssen E, Huwyler J, Porter R, Spooren W | title = The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison | journal = Psychopharmacology | volume = 179 | issue = 1 | pages = 218–29 | date = April 2005 | pmid = 15739074 | doi = 10.1007/s00213-005-2211-9 | s2cid = 25136496 }}{{cite journal | vauthors = 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 | display-authors = 6 | title = 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 | journal = Psychopharmacology | volume = 179 | issue = 1 | pages = 207–17 | date = April 2005 | pmid = 15682298 | doi = 10.1007/s00213-005-2143-4 | s2cid = 21807900 }} and to reduce the effects of morphine withdrawal,{{cite journal | vauthors = Rasmussen K, Martin H, Berger JE, Seager MA | title = The mGlu5 receptor antagonists MPEP and MTEP attenuate behavioral signs of morphine withdrawal and morphine-withdrawal-induced activation of locus coeruleus neurons in rats | journal = Neuropharmacology | volume = 48 | issue = 2 | pages = 173–80 | date = February 2005 | pmid = 15695156 | doi = 10.1016/j.neuropharm.2004.09.010 | s2cid = 13552709 }} most likely due to direct interaction between mGluR5 and the μ-opioid receptor.{{cite journal | vauthors = Schröder H, Wu DF, Seifert A, Rankovic M, Schulz S, Höllt V, Koch T | title = Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the micro-opioid receptor | journal = Neuropharmacology | volume = 56 | issue = 4 | pages = 768–78 | date = March 2009 | pmid = 19162047 | doi = 10.1016/j.neuropharm.2008.12.010 | s2cid = 41530896 }}

The main significance of MPEP has been as a lead compound to develop more potent and selective mGluR5 antagonists such as MTEP,{{cite journal | vauthors = Lea PM, Faden AI | title = Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP | journal = CNS Drug Reviews | volume = 12 | issue = 2 | pages = 149–66 | year = 2006 | pmid = 16958988 | pmc = 6494124 | doi = 10.1111/j.1527-3458.2006.00149.x }} but research using MPEP itself continues, and recently it was shown to reduce self-administration of nicotine,{{cite journal | vauthors = Paterson NE, Semenova S, Gasparini F, Markou A | title = The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice | journal = Psychopharmacology | volume = 167 | issue = 3 | pages = 257–64 | date = May 2003 | pmid = 12682710 | doi = 10.1007/s00213-003-1432-z | s2cid = 40627145 }}{{cite journal | vauthors = Bespalov AY, Dravolina OA, Sukhanov I, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A | display-authors = 6 | title = Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats | journal = Neuropharmacology | volume = 49 | pages = 167–78 | year = 2005 | issue = Suppl 1 | pmid = 16023685 | doi = 10.1016/j.neuropharm.2005.06.007 | s2cid = 37283433 }} cocaine,{{cite journal | vauthors = Tessari M, Pilla M, Andreoli M, Hutcheson DM, Heidbreder CA | title = Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking | journal = European Journal of Pharmacology | volume = 499 | issue = 1–2 | pages = 121–33 | date = September 2004 | pmid = 15363959 | doi = 10.1016/j.ejphar.2004.07.056 }}{{cite journal | vauthors = Paterson NE, Markou A | title = The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats | journal = Psychopharmacology | volume = 179 | issue = 1 | pages = 255–61 | date = April 2005 | pmid = 15619120 | doi = 10.1007/s00213-004-2070-9 | s2cid = 24096619 }} ketamine and heroin in animals,{{cite journal | vauthors = van der Kam EL, de Vry J, Tzschentke TM | title = Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat | journal = Behavioural Pharmacology | volume = 18 | issue = 8 | pages = 717–24 | date = December 2007 | pmid = 17989509 | doi = 10.1097/FBP.0b013e3282f18d58 | s2cid = 24990842 }} possibly through an MPEP-induced potentiation of the rewarding effect of the self-administered drug,{{cite journal | vauthors = van der Kam EL, De Vry J, Tzschentke TM | title = 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 | journal = European Journal of Pharmacology | volume = 606 | issue = 1–3 | pages = 94–101 | date = March 2009 | pmid = 19210976 | doi = 10.1016/j.ejphar.2008.12.042 }} and MPEP was also shown to possess weak reinforcing effects by itself.{{cite journal | vauthors = van der Kam EL, De Vry J, Tzschentke TM | title = The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intravenous self-administration and induces conditioned place preference in the rat | journal = European Journal of Pharmacology | volume = 607 | issue = 1–3 | pages = 114–20 | date = April 2009 | pmid = 19326478 | doi = 10.1016/j.ejphar.2009.01.049 }}