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Name: Dipraglurant
Synonyms: ADX48621
Chemical Name: 6-Fluoro-2-[4-(2-pyridinyl)-3-butyn-1-yl]imidazo[1,2-a]pyridine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2/3)
Company: Addex Therapeutics


This is a negative allosteric modulator of the mGluR5 metabotropic glutamate receptor, taken by mouth. It is being developed for the treatment of levodopa-induced dyskinesia (LID) associated with Parkinson’s disease. Dyskinesias are uncontrollable, sometimes disabling, muscle contractions brought on by therapeutic doses of levodopa. Dipraglurant reduces the abnormal glutamate signaling that contributes to dyskinesia. The only drug approved to treat LID is amantadine, which also blocks glutamate signaling.

In preclinical work, dipraglurant rendered LID less severe in a macaque model of PD, without reducing levodopa’s efficacy (Bezard et al., 2014). Dipraglurant also reduced involuntary muscle contractions in a mouse model of dystonia, by restoring brain synaptic plasticity (Sciamanna et al., 2014Martella et al., 2021).

MGluR5 antagonists are of interest in Alzheimer’s, as well, because the receptor is involved in neuron and astrocyte responses to Aβ (Renner et al., 2010; Um et al., 2013; Shrivastava et al., 2013). In mouse models of AD, mGluR5 inhibitors protect memory and reduce amyloid deposition (Hamilton et al., 2016). MGluR5 has also been reported to mediate α-synuclein-induced cognitive impairments in an α-synuclein transgenic mouse model of PD (Ferreira et al., 2017).

In the 2000s, at least three companies besides Addex were developing mGluR5 negative allosteric modulators for indications including Fragile X syndrome, anxiety, major depression, and LID. The programs were stopped for lack of efficacy, dose-limiting side effects, or liver toxicity.


Addex completed a Phase 2a trial for Parkinson’s Disease LID in 2012. Conducted in the United States and Europe, it enrolled 76 people with moderate to severe LID, who received dipraglurant for 28 days, taken at the same time as levodopa. The dose was titrated from 50 mg once daily to 100 mg three times daily over 21 days, and fixed at 100 mg for the last seven days. The primary endpoint was safety. Clinical endpoints included severity of dyskinesia rated on the modified Abnormal Involuntary Movement Scale on days one, 14, and 28, plus the Unified Parkinson Disease Rating Scale, Clinical Global Impression of Change (CGIC), and patient diaries.

The trial met its primary endpoints of safety and tolerability. The treatment group had more severe adverse events than the placebo group; two participants discontinued due to adverse events at 100 mg. Most common were dizziness, nausea, fatigue, and worsening dyskinesia between doses. On clinical endpoints, the treated group saw a 30 percent improvement of dyskinesia compared to placebo. The difference was statistically significant on days one and 14, but not 28. No differences were observed on UPRDS or patient-reported outcomes. The CGIC was improved in 71.2 percent of the treated group compared to 49.9 percent in placebo. Results are published (Tison et al., 2016).

In 2015, the company conducted a Phase 1 PET study  to measure mGluR5 receptor occupancy kinetics in 12 healthy adults. According to an April 2016 press release, dipraglurant receptor binding was dose-proportional, with 27 percent occupancy after a 100 mg dose, 44.4 percent after 200 mg, and 53.5 percent after 300 mg. A range of 50 to 70 percent occupancy is claimed to give an optimal anti-dyskinetic effect.

In January 2016, dipraglurant received orphan drug designation from the United States FDA for the treatment of LID (press release).

In August 2021, Addex began a three-month Phase 2b/3 trial in PD patients with LID. The 140 participants will take 150 mg per day for one week, then 300 mg daily for the rest of the study, or placebo. The study includes a 12-month open label extension. The primary endpoint will be change in the Unified Dyskinesia Rating scale, a measure developed specifically to assess LID. Secondary endpoints are ON and OFF time based on patient diaries. Completion is slated for August 2023.

The company is also conducting a Phase 2 feasibility study in 15 people with blepharospasm, a form of dystonia that affects the eyelid muscles and can cause vision problems. Data is expected in mid-2022.

For details on dipraglurant trials, see

Last Updated: 07 Apr 2022


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Paper Citations

  1. . A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease. Mov Disord. 2016 Sep;31(9):1373-80. Epub 2016 May 23 PubMed.
  2. . The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model. Mov Disord. 2014 Jul;29(8):1074-9. Epub 2014 May 27 PubMed.
  3. . Negative allosteric modulation of mGlu5 receptor rescues striatal D2 dopamine receptor dysfunction in rodent models of DYT1 dystonia. Neuropharmacology. 2014 Oct;85:440-50. Epub 2014 Jun 19 PubMed.
  4. . Rescue of striatal long-term depression by chronic mGlu5 receptor negative allosteric modulation in distinct dystonia models. Neuropharmacology. 2021 Jul 1;192:108608. Epub 2021 May 13 PubMed.
  5. . Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. 2010 Jun 10;66(5):739-54. PubMed.
  6. . Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron. 2013 Sep 4;79(5):887-902. PubMed.
  7. . β-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors. Glia. 2013 Oct;61(10):1673-86. PubMed.
  8. . Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model. Cell Rep. 2016 May 31;15(9):1859-65. Epub 2016 May 19 PubMed.
  9. . α-synuclein interacts with PrP(C) to induce cognitive impairment through mGluR5 and NMDAR2B. Nat Neurosci. 2017 Nov;20(11):1569-1579. Epub 2017 Sep 25 PubMed.

External Citations

  1. April 2016 press release
  2. press release

Further Reading


  1. . Effects of mGluR5 Antagonists on Parkinson's Patients With L-Dopa-Induced Dyskinesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Aging Neurosci. 2018;10:262. Epub 2018 Sep 11 PubMed.
  2. . Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. Parkinsonism Relat Disord. 2014 Sep;20(9):947-56. Epub 2014 May 14 PubMed.
  3. . Understanding exposure-receptor occupancy relationships for metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators across a range of pre-clinical and clinical studies. J Pharmacol Exp Ther. 2021 Feb 4; PubMed.
  4. . Detailed In Vitro Pharmacological Characterization of Clinically Tested Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5. Mol Pharmacol. 2020 Jul;98(1):49-60. Epub 2020 May 1 PubMed.
  5. . Understanding exposure-receptor occupancy relationships for metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators across a range of pre-clinical and clinical studies. J Pharmacol Exp Ther. 2021 Feb 4; PubMed.
  6. . Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology. Neuropharmacology. 2019 May 1;149:83-96. Epub 2019 Feb 11 PubMed.
  7. . Exploring the Binding Mechanism of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators in Clinical Trials by Molecular Dynamics Simulations. ACS Chem Neurosci. 2018 Jun 20;9(6):1492-1502. Epub 2018 Mar 16 PubMed.