Objective/Rationale:
mGluR3 is a protein and target for neuroprotection. We have recently demonstrated that selective mGluR3 positive allosteric modulators (PAMs) mimic neuroprotective effects and production of neurotrophic factors (proteins that grow and protect neurons) induced by mGluR3 activation. The goals of the current project are to nominate an mGluR3 PAM candidate for pre-clinical testing and to perform a proof-of-efficacy study.
Project Description:
The project consists in three separate phases:
First, several mGluR3 PAM candidates with optimized potencies and selectivity/stability profiles will be further characterized in pharmacokinetic (PK) studies. In parallel, these candidates will be profiled for their neuroprotective and neurotrophic factor production activities using primary neurons from the cortex and the striatum.
The two candidates showing the best combination of potencies and PK profile will be further characterized in models after oral administration for their capacity to modulate levels of neurotrophic factors.
Finally, neuroprotective activity of the most promising candidate will be evaluated in pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In addition to having robust neuroprotective activity, neurotrophic factors have been shown to exert motor improvements in Parkinson’s disease. The possibility to orally enhance neurotrophic factor levels with small mGluR3 PAMs would be a real breakthrough in the treatment of the Parkinson’s disease.
Anticipated Outcome:
The stimulating activity of mGluR3 activation on neurotrophic factor production, together with the fact that mGluRs agonists are well tolerated in clinical studies make this novel neuroprotective mechanism very attractive. If found successful, candidates with proof of efficacy in pre-clinical models will advance to clinical testing.
Progress Report
The goals of the present research grant were:
- to nominate at least one candidate with suitable pharmacokinetic and in vitro neuroprotective / GDNF-production activities for pre-clinical proof-of-concept studies
- to generate a genetic model lacking mGluR3 to be used in the proof-of-concept studies
We have successfully completed the characterization of five optimized leads and nominated one candidate to be further evaluated in model. This molecule shows excellent PK parameters, including blood-brain barrier penetration. The second part of the work has been initiated and first genetically modified models are expected for mid-2015 for proof-of-concept studies.
Presentations & Publications
Stephan Schann. mGluR3 PAM as novel neuroprotective therapeutic strategy for Parkinson's Disease. Oral presentation, 8th International Meeting on Metabotropic Glutamate Receptors, Taormina, Italy. Oct 03, 2014
Stephan Schann1, Stanislas Mayer1, Christel Franchet1, Mélanie Frauli1, Sophie Scheffler1, Thierry Pillot2, Baptiste Manteau1, Pascal Neuville1 mGluR3 PAM: Novel Neuroprotective Therapeutic Strategy for Parkinson's Disease. In vitro neuroprotection and neurotrophic factor production Poster. SfN 2014 meeting, Washington, DC. Nov 16, 2014
Baptiste Manteau, Stephan Schann, Stanislas Mayer. Discovery and optimization of selective mGluR3 PAMs towards novel neuroprotective agents for the treatment of Parkinson's disease. Poster. 2014 ACS National meeting, San Francisco, CA. Aug 11, 2014; Aug 13, 2014
January 2015