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Review

mGlu5 negative allosteric modulators: a patent review (2013 - 2016)

Pages 691-706 | Received 11 Nov 2016, Accepted 06 Jan 2017, Published online: 19 Jan 2017

References

  • Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol. 2010;50:295–322.
  • Lindsley CW, Emmitte KA, Hopkins CR, et al. Practical strategies and concepts in GPCR allosteric modulator discovery: recent advances with metabotropic glutamate receptors. Chem Rev. 2016;116:6707–6741.
  • Emmitte KA. mGlu5 negative allosteric modulators: a patent review (2010-2012). Expert Opin Ther Pat. 2013;23:393–408.
  • Emmitte KA. Recent advances in the design and development of novel negative allosteric modulators of mGlu(5). ACS Chem Neurosci. 2011;2:411–432.
  • Rocher J-P, Bonnet B, Boléa C, et al. mGluR5 negative allosteric modulators overview: a medicinal chemistry approach towards a series of novel therapeutic agents. Curr Top Med Chem. 2011;11:680–695.
  • Jaeschke G, Wettstein JG, Nordquist RE, et al. mGlu5 receptor antagonists and their therapeutic potential. Expert Opin Ther Pat. 2008;18:123–142.
  • Bach P, Isaac M, Slassi A. Metabotropic glutamate receptor 5 modulators and their potential therapeutic applications. Expert Opin Ther Pat. 2007;17:371–384.
  • Mihov Y, Hasler G. Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window. Int J Neuropsychopharmacol. 2016 ;19:1–11.
  • Tronci V, Vronskaya S, Montgomery N, et al. The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on behavioural responses to nicotine. Psychopharmacology. 2010;211:33–42.
  • Adams CL, Short JL, Lawrence AJ. Cue-conditioned alcohol seeking in rats following abstinence: involvement of metabotropic glutamate 5 receptors. Br J Pharmacol. 2010;159:534–542.
  • Martin-Fardon R, Baptista MAS, Dayas CV, et al. Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer. J Pharmacol Exp Ther. 2009;329:1084–1090.
  • Gass JT, Osborne MPH, Watson NL, et al. mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats. Neuropsychopharmacology. 2009;34:820–833.
  • Besheer J, Grondin JJM, Salling MC, et al. Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci. 2009;29:9582–9591.
  • Gass JT, Olive MF. Role of protein kinase C epsilon (PKCɛ) in the reduction of ethanol reinforcement due to mGluR5 antagonism in the nucleus accumbens shell. Psychopharmacology. 2009;204:587–597.
  • Kumaresan V, Yuan M, Yee J, et al. Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res. 2009;202:238–244.
  • Platt DM, Rowlett JK, Spealman RD. Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: comparison with dizocilpine. Psychopharmacology. 2008;200:167–176.
  • Iso Y, Grajkowska E, Wroblewski JT, et al. Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications. J Med Chem. 2006;49:1080–1100.
  • Kenny PJ, Boutrel B, Gasparini F, et al. Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology. 2005;179:247–254.
  • Lee B, Platt DM, Rowlett JK, et al. Attenuation of behavioral effects of cocaine by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine. J Pharmacol Exp Ther. 2005;312:1232–1240.
  • Tessari M, Pilla M, Andreoli M, et al. Antagonism at metabotropic glutamate 5 receptor inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur J Pharmacol. 2004;499:121–133.
  • McGeehan AJ, Olive MF. The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine but not other drugs of abuse. Synapse. 2003;47:240–242.
  • Lindemann L, Porter RH, Scharf SH, et al. Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther. 2015;353:213–233.
  • Jaeschke G, Kolczewski S, Spooren W, et al. Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases. J Med Chem. 2015;58:1358–1371.
  • Felts AS, Rodriguez AL, Morrison RD, et al. Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety. Bioorg Med Chem Lett. 2013;23:5779–5785.
  • Carcache D, Vranesic I, Blanz J, et al. Benzimidazoles as potent and orally active mGlu5 receptor antagonists with an improved PK profile. ACS Med Chem Lett. 2010;2:58–62.
  • Busse CS, Brodkin J, Tattersall D, et al. The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology. 2004;29:1971–1979.
  • Klodzinska A, Tatarczyńska E, Chojnacka-Wójcik E, et al. Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABAA signaling. Neuropharmacology. 2004;47:342–350.
  • Spooren WPJM, Vassout A, Neijt HC, et al. Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents. J Pharmacol Exp Ther. 2000;295:1267–1275.
  • Pop AS, Gomez-Mancilla B, Neri G, et al. Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development. Psychopharmacol (Berl). 2014;231:1217–1226.
  • Thomas AM, Bui N, Perkins JR, et al. Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome. Psychopharmacol (Berl). 2012;219:47–58.
  • Michalon A, Sidorov M, Ballard TM, et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron. 2012;74:49–56.
  • Levenga J, Hayashi S, De Vrij FM, et al. AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol Dis. 2011;42:311–317.
  • de Vrij FMS, Levenga J, Van der Linde HC, et al. Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis. 2008;31:127–132.
  • Yan QJ, Rammal M, Tranfaglia M, et al. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005;49:1053–1066.
  • Picconi B, Calabresi P. Targeting metabotropic glutamate receptors as a new strategy against levodopa-induced dyskinesia in Parkinson’s disease? Mov Disord. 2014;29:715–719.
  • Rascol O, Fox S, Gasparini F, et al. Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. Parkinsonism Relat Disord. 2014;20:947–956.
  • Zhang L, Balan G, Barreiro G, et al. Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator. J Med Chem. 2014;57:861–877.
  • Grégoire L, Morin N, Ouattara B, et al. The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-Dopa-treated parkinsonian monkeys. Parkinsonian Rel Disord. 2011;17:270–276.
  • Rylander D, Iderberg H, Li Q, et al. A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys. Neurobiol Dis. 2010;39:352–361.
  • Morin N, Grégoire L, Gomez-Mancilla B, et al. Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys. Neuropharmacology. 2010;58:981–986.
  • Breysse N, Baunez C, Spooren W, et al. Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J Neurosci. 2002;22:5669–5678.
  • Overk CR, Cartier A, Shaked G, et al. Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5 – implications for dementia with Lewy bodies. Mol Neurodegener. 2014;9:18.
  • Hamilton A, Esseltine JL, DeVries RA, et al. Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer’s disease. Mol Brain. 2014;7:40.
  • Um JW, Kaufman AC, Kostylev M, et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron. 2013;79:887–902.
  • Chung W, Choi SY, Lee E, et al. Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. Nat Neurosci. 2015;18:435–443.
  • Silverman JL, Smith DG, Rizzo SJ, et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med. 2012;4:131ra51.
  • Silverman JL, Tolu SS, Barkan CL, et al. Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology. 2010;35:976–989.
  • Hughes ZA, Neal SJ, Smith DL, et al. Negative allosteric modulation of metabolic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology. 2013;66:202–214.
  • Tatarczyńska E, Kłodzińska A, Chojnacka-Wójcik E, et al. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol. 2001;132:1423–1430.
  • Dipraglurant structure disclosed in International nonproprietary names for pharmaceutical substances (INN). WHO Drug Inf. 2009;23:271–367.
  • Vranesic I, Ofner S, Flor PJ, et al. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014;22:5790–5803.
  • Gasparini F, Lingenhöhl K, Stoehr N, et al. Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systematically active mGlu5 receptor antagonist. Neuropharmacology. 1999;38:1493–1503.
  • Cosford ND, Tehrani L, Roppe J, et al. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem. 2003;46:204–206.
  • Walles M, Wolf T, Jin Y, et al. Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects. Drug Metab Dispos. 2013;41:1626–1641.
  • Guerini E, Schadt S, Greig G, et al. A double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]-basimglurant and absolute bioavailability after oral administration and concomitant intravenous microdose administration of [13C6]-labeled basimglurant in humans. Xenobiotica. 2016. [Epub ahead of print]. DOI:10.3109/00498254.2016.1169334
  • Jacquemont S, Curie A, Des Portes V, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3:64ra1.
  • Berry-Kravis E, Des Portes V, Hagerman R, et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med. 2016;8:321ra5.
  • Bailey DB Jr, Berry-Kravis E, Wheeler A, et al. Mavoglurant in adolescents with fragile X syndrome: analysis of Clinical Global Impression-Improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study. J Neurodev Disord. 2016;8:1. DOI:10.1186/s11689-015-9134-5
  • Quiroz J, Wasef E, Wong CY, et al. Effect of two doses of basimglurant on behavioral symptoms in adolescent and adult patients with Fragile X Syndrome; results from Fragxis, a double-blind, placebo controlled study. Presented at 2015 International Meeting for Autism Research; 2015 May 15; Salt Lake City, UT.
  • Mullard A. Fragile X disappointments upset autism ambitions. Nat Rev Drug Discov. 2015;14:151–153.
  • AFQ056 for language learning in children with FXS. ClinicalTrials.gov. Bethesda, MA: U.S. National Institutes of Health. [ cited 2016 Oct 21]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02920892
  • Berg D, Godau J, Trenkwalder C, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011 Jun;26(7):1243–1250.
  • Stocchi F, Rascol O, Destee A, et al. AFQ056 in Parkinson patients with levodopa-induced dyskinesia: 13-Week, randomized, dose-finding study. Mov Disord. 2013 Nov;28(13):1838–1846.
  • Kumar R, Hauser RA, Mostillo J, et al. Mavoglurant (AFQ056) in combination with increased levodopa dosages in Parkinson’s disease patients. Int J Neurosci. 2016;126(1):20–24.
  • Stocchi F, Balaguer E, Trenkwalder C, et al. 12-week, double-blind, placebo-controlled, fixed-dose study of immediate release AFQ056, an mGluR5 receptor antagonist, in Parkinson’s disease patients with moderate-to-severe L-dopa induced dyskinesias [abstract]. Move Disord. 2014;29 Suppl 1:723.
  • Trenkwalder C, Kulisevsky J, Poewe W, et al. 13-week, double-blind, placebo-controlled, fixed-dose study of modified release AFQ056, an mGluR5 receptor antagonist, in Parkinson’s disease patients with moderate-to-severe L-dopa induced dyskinesias [abstract]. Move Disord. 2014;29 Suppl 1:733.
  • Petrov D, Pedros I, De Lemos ML, et al. Mavoglurant as a treatment for Parkinson’s disease. Expert Opin Investig Drugs. 2014;23:1165–1179.
  • Tison F, Keywood C, Wakefield M, et al. A phase 2A trial of the novel mGluR5-negative allosteric modulator dipraglurant for levodopa-induced dyskinesia in Parkinson’s disease. Mov Disord. 2016;31:1373–1380.
  • Addex Therapeutics press release: addex’ dipraglurant receives orphan drug designation from the FDA for levodopa-induced dyskinesia associated with Parkinson’s disease. Geneva (Switzerland). 2016 Jan 4.
  • Wong DF, Waterhouse R, Kuwabara H, et al. 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med. 2013 Mar;54(3):388–396.
  • Addex Therapeutics press release: addex reports positive results of an mGlu5 receptor occupancy study with dipraglurant in healthy volunteers. Geneva (Switzerland). 2016 Apr 11.
  • Fuxe K, Borroto-Escuela DO. Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5. Expert Opin Investig Drugs. 2015;24:1247–1260.
  • Quiroz JA, Tamburri P, Deptula D, et al. Efficacy and safety of basimglurant as adjunctive therapy for major depression: a randomized clinical trial. JAMA Psychiatry. 2016;73:675–684.
  • Pharma Pipeline F Hoffman-La Roche, Ltd. Basel (Switzerland): Roche Product Development Portfolio. [ Updated 2016 Oct 20; cited 2016 Oct 24]. Available from: http://www.roche.com/research_and_development/who_we_are_how_we_work/pipeline.htm
  • Novartis AG. Modified release formulation. WO2014199316. 2014.
  • Addex Pharma SA. Extended release formulations. WO2013186311. 2013.
  • Addex Pharma SA. Pharmaceutical combination products for Parkinson’s disease. WO2013139941. 2013.
  • Addex Pharma SA. Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2a]pyridine and polymorphs thereof as negative allosteric modulator of mGlu5 receptor. WO 2015044270. 2015.
  • F Hoffman Laroche AG. Ethynyl derivatives as modulators of mGluR5 receptor activity. WO 2014060384. 2014.
  • F Hoffman LaRoche AG. Ethynyl derivatives as modulators of mGluR5 receptor activity. WO 2014060394. 2014.
  • F Hoffman LaRoche AG. Ethynyl derivatives as modulators of mGluR5 receptor activity. WO 2014060398. 2014.
  • Wood MR, Hopkins CR, Brogan JT, et al. “Molecular switches” on mGluR allosteric ligands that modulate modes of pharmacology. Biochem. 2011;50:2403–2410.
  • F Hoffman Laroche AG. Ethynyl derivatives as metabotropic glutamate receptor antagonists. WO 2015004007. 2015.
  • Merz Pharma GmbH & Co KGaA. Heterocyclic derivatives as metabotropic glutamate receptor modulators. EP2650284. 2013.
  • Merz Pharma GmbH & Co KGaA. Metabotropic glutamate receptor modulators. WO2012052451. 2012.
  • H Lundbeck A/S. Bicarboxylic and tricarboxylic ethynyl derivatives and uses of same. WO 2013040535. 2013.
  • H Lundbeck A/S. Bicyclo[3.2.1]octyl amide derivatives and uses of same. WO 2012088365. 2012.
  • H Lundbeck A/S. Adamantyl amide derivatives and uses of same. WO 20110087758. 2011.
  • H Lundbeck A/S. Adamantyl amide derivatives and uses of same. WO 2010011570. 2010.
  • O’Brien JA, Lemaire W, Chen T-B, et al. A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol. 2003;64:731–740.
  • Hua Medicine (Shanghai) Ltd. mGluR regulators. WO 2014124560. 2014.
  • Korea Institute of Science and Technology. 2-(Substituted ethynyl)quinoline derivatives as mGluR5 antagonists. US20140206876. 2014.
  • Kim SH, Na HS, Sheen K, et al. Effects of sympathectomy on a rat model of peripheral neuropathy. Pain. 1993;55:85–92.
  • Toray Industries, Inc. Imidazo[1,2-a]pyridine derivatives and use thereof for medical purposes. WO 2013081094. 2013.
  • Carcache D, Vranesic I, Blanz J, et al. Benzimidazoles as potent and orally active mGlu5 receptor antagonists with an improved PK profile. ACS Med Chem Lett. 2011;2:58–62.
  • Toray Industries, Inc. N-Alkylamide derivative and medicinal use thereof. WO 2015098991. 2015.
  • Satow A, Maehara S, Ise S, et al. Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC, [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]. J Pharmacol Exp Ther. 2008;326:577–586.
  • Togashi Y, Umeuchi H, Okano K, et al. Antipruritic activity of the κ-opioid receptor agonist, TRK-820. Eur J Pharmacol. 2002;435:259–264.
  • Montana MC, Gereau RW IV. Metabotropic glutamate receptors as targets for analgesia: antagonism, activation, and allosteric modulation. Curr Pharm Biotechnol. 2011;12:1681–1688.
  • Dainippon Sumitomo Pharma Co Ltd. Tetrahydrooxazolopyridine derivative. JP 2014185092 (2014)
  • Burdi DF, Hunt R, Fan L, et al. Design, synthesis, and structure−activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5. J Med Chem. 2010;53:7107–7118.
  • Dainippon Sumitomo Pharma Co., Ltd. Completes Acquisition of Sepracor Inc. Dainippon Sumitomo Pharma Co., Ltd. Osaka (Japan): News Releases. [ cited 2016 Oct 31]. Available from: http://www.ds-pharma.com/news/192009/20091021.html
  • Youdim MBH, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci. 2006;7:295–309.
  • Dainippon Sumitomo Pharma Co Ltd. Tetrahydrooxazolo-pyridine derivative. WO 2014065270. 2014.
  • Dainippon Sumitomo Pharma Co Ltd. Tetrahydopyrazolopyrazine derivatives. JP 2015059118. 2015.
  • Nippon Shinyaku Co Ltd. Pyridine derivative and medicine. WO 2014034898. 2014.
  • Hunskaar S, Hole K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain. 1987;30:103–114.
  • Oyama T, Homan T, Kyotani J, et al. Effect of tramadol on pain-related behaviors and bladder overactivity in rodent cystitis models. Eur J Pharmacol. 2012;676:75–80.
  • Boehringer Ingelheim International GMBH. Novel pyrazolopyrimidines. WO 2013144172. 2013.
  • Novo Nordisk A/S. New pyrazolo[1,5-a]pyrimidines derivatives and pharmaceutical uses thereof. WO 2004089471. 2004.
  • Merz Pharma GMBH & Co KGAA. Enteric formulations of metabotropic glutamate receptor modulators. WO 2012139876. 2012.
  • Merz Pharma GMBH & Co KGAA. Substituted pyrazolopyrimidines, a process for their preparation and their use as medicine. WO 2008015269. 2008.
  • Novartis AG Diazepinone derivatives useful for the treatment of fragile X syndrome, Parkinson’s or reflux disease. WO 2014030128. 2014.
  • Heptares Therapeutics Ltd. 4-(3-Cyanophenyl)-6-pyridinylpyrimidine mGlu5 modulators. WO 2015008073. 2015.
  • Gasparini F, Andres H, Flor PJ, et al. [3H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett. 2002;12:407–409.
  • Deacon RMJ. Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protocols. 2006;1:122–124.
  • Vanderbilt University. Substituted 4-alkoxypicolinamide analogs as mGluR5 negative allosteric modulators. WO 2015200682. 2015.
  • Vanderbilt University. Substituted imidazopyridine and triazolopyridine compounds as negative allosteric modulators of mGluR5. WO 2015077246. 2015.
  • Vanderbilt University. Substituted 6-aryl-imidazopyridine and 6-aryl-triazolopyridine carboxamide analogs as negative allosteric modulators of mGluR5. US 20160096833. 2016.
  • Vanderbilt University. Substituted bicyclic heteroaryl carboxamide analogs as mGluR5 negative allosteric modulators. US 20150266866. 2015.
  • Vanderbilt University. 6-Alkyl-N-(pyridin-2-yl)-4-aryloxypicolinamide analogs as mGluR5 negative allosteric modulators and methods of making and using the same. WO 2012118563. 2012.
  • Swedberg MDB, Raboisson P. AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects. J Pharmacol Exp Ther. 2014;350:212–222.
  • Homayoun H, Stefani MR, Adams BW, et al. Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology. 2004;29:1259–1269.
  • Kinney GG, Burno M, Campbell UC, et al. Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther. 2003;306:116–123.
  • Porter RH, Jaeschke G, Spooren W, et al. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther. 2005;315:711–721.
  • Nickols HH, Yuh JP, Gregory KJ, et al. VU0477573: partial negative allosteric modulator of the subtype 5 metabotropic glutamate receptor with in vivo efficacy. J Pharmacol Exp Ther. 2016;356:123–136.
  • Gould RW, Amato RJ, Bubser M, et al. Partial mGlu5 negative allosteric modulators attenuate cocaine-mediated behaviors and lack psychotomimetic-like effects. Neuropsychopharmacology. 2016;41:1166–1178.
  • Palanisamy GS, Marcek JM, Cappon GD, et al. Drug-induced skin lesions in cynomolgus macaques treated with metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators. Toxicol Pathol. 2015;43(7):995–1003.
  • Morin N, Morissette M, Grégoire L, et al. Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys. Neuropharmacology. 2013;73:216–231.
  • Masilamoni GJ, Bogenpohl JW, Alagille D, et al. Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Brain. 2011;134:2057–2073.

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