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Therapeutic potential of targeting glutamate receptors in Parkinson’s disease

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
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Abstract

Glutamate plays a complex role in many aspects of Parkinson’s disease including the loss of dopaminergic neurons, the classical motor symptoms as well as associated non-motor symptoms and the treatment-related side effect, l-DOPA-induced dyskinesia. This widespread involvement opens up possibilities for glutamate-based therapies to provide a more rounded approach to treatment than is afforded by current dopamine replacement therapies. Beneficial effects of blocking postsynaptic glutamate transmission have already been noted in a range of preclinical studies using antagonists of NMDA receptors or negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), while positive allosteric modulators of mGlu4 in particular, although at an earlier stage of investigation, also look promising. This review addresses each of the key features of Parkinson’s disease in turn, summarising the contribution glutamate makes to that feature and presenting an up-to-date account of the potential for drugs acting at ionotropic or metabotropic glutamate receptors to provide relief. Whilst only a handful of these have progressed to clinical trials to date, notably NMDA and NR2B antagonists against motor symptoms and l-DOPA-induced dyskinesia, with mGlu5 negative allosteric modulators also against l-DOPA-induced dyskinesia, the mainly positive outcomes of these trials, coupled with supportive preclinical data for other strategies in animal models of Parkinson’s disease and l-DOPA-induced dyskinesia, raise cautious optimism that a glutamate-based therapeutic approach will have significant impact on the treatment of Parkinson’s disease.

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Acknowledgments

SD has received grant funding/research support on projects relating to glutamate in Parkinson’s disease from the Wellcome Trust, UK Medical Research Council, Guy’s King’s and St Thomas’ Charitable trustees, Parkinson’s UK, and Centre for Integrative Biomedicine at King’s College London, However, no sources of funding have been used to prepare this review. CF holds an MRC CASE Studentship with Eli Lilly and Co Ltd.

Conflict of interest

There are no conflicts of interest to note.

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  1. Wolfson Centre for Age-Related Diseases, King’s College London, WW1.28. Hodgkin Building, Guy’s Campus, London, SE1 1UL, UK

    Clare Finlay & Susan Duty

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Correspondence to Susan Duty.

Chemical names of glutamatergic drugs by pharmacological class

Chemical names of glutamatergic drugs by pharmacological class

AMPA receptor antagonists (*mixed AMPA/Kainate antagonist): IEM-1460, N,N,H,-trimethyl-5-[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]-1-pentanaminiumbromide hydrobromide; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline -7-sulfonamide; *talampanel (LY300164), (8R)-7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; topiramate, 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate.

AMPA receptor potentiators: LY404187, N-[2-(4′-cyanobiphenyl-4-yl)propyl]propane-2-sulfonamide; LY503430, 4′-{(1S)-1-fluoro-2-[(isopropylsulfonyl)amino]-1-methylethyl}-N-methylbiphenyl-4-carboxamide.

NMDA receptor antagonists: amantadine, adamantan-1-amine; AZD6765 (lanicemine), (1S)-1-Phenyl-2-pyridin-2-ylethanamine; CPP, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; ketamine, (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone; memantine, 3,5-dimethyladamantan-1-amine; MDL-100,453, [R]-4-oxo-5-phosphononorvaline; MK-801 (dizocilpine), [5R,10S]-[+]-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.

NR2B-selective NMDA receptor antagonists: BZAD-01, 4-trifluoromethoxy-N-(2-trifluoromethyl-benzyl)-benzamidine: CI-1041 (besonprodil), 6-[2-(4-[(4-fluorophenyl)methyl]piperidin-1-yl)ethylsulfinyl]-3H-1,3-benzoxazol-2-one; Co-101244 (Ro 63-1908), 1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]-4-piperidinol hydrochloride; ifenprodil, 4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol; MK-0657, (3S,4R)-4-methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate; Ro 25-6981, (αR,βS)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol; traxoprodil (CP-101,606), (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol.

Group II mGlu receptor agonists: DCG-IV, (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine; LY354740, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY379268, (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid.

mGlu2 receptor positive allosteric modulators (PAMs): THIIC, N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methy l-1H-imidazole-4-carboxamide; 4-MPPTS (LY487379), N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine.

Group III mGlu receptor agonists: ACPT-I, (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid; L-AP4, L-(+)-2-amino-4-phosphonobutyric acid.

mGlu4 receptor agonist. LSP1-2111, (2S)-2-amino-4-(hydroxyl(hydroxyl(4-hydroxy-3-methoxy-5-nitrophenyl)-methyl)phosphoryl)butanoic acid.

mGlu4 receptor PAMs: Lu AF21934, (1S,2R)-2-[(aminooxy)methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamide; PHCCC, (−)-N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide; VU0155041, cis-2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanecarboxylic acid.

mGlu8 receptor agonist: (S)-DCPG, (S)-3,4-dicarboxyphenylglycine.

mGlu5 receptor antagonists or NAMS (negative allosteric modulators): ADX48621 (dipraglurant), 2-(4-{6-fluoroimidazo[1,2-a]pyridin-2-yl}but-1-yn-1-yl)pyridine; AFQ056 (mavoglurant), methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate; fenobam, 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4H-imidazol-2-yl)urea; MPEP, 2-methyl-6-(phenylethynyl) pyridine; MTEP, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine.

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Finlay, C., Duty, S. Therapeutic potential of targeting glutamate receptors in Parkinson’s disease. J Neural Transm 121, 861–880 (2014). https://doi.org/10.1007/s00702-014-1176-4

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