Objective/Rationale:
mGluR3 is a novel target that could lead to neuroprotection through production of GDNF and TGF-beta in striatal neurons. The goals of the current project are first to optimize existing submicromolar and selective leads into candidates for in vivo studies, and second, to characterize the neuroprotective role of these molecules using in vitro models.
Project Description:
The project will consist in the optimization of existing selective mGluR3 PAM (positive allosteric modulator) leads into candidates that will be suitable for evaluation in in vivo models of Parkinson’s disease. PAMs bind to the target protein at a different location than the receptor, and increase signal transduction that results from receptor activation. In particular, special attention will be paid during the optimization process to keep high selectivity over the close mGluR2 subtype that was shown in vitro to be neurotoxic upon activation. These mGluR3 PAMs will also be used for in vitro neuroprotection test and for in vitro GDNF and TGF-beta production assessments using cell cultures from both wild-type and mGluR3 KO mice. These in vitro evaluations will be performed by the team of D.r Valeria Bruno at the Neuromed Institute in Pozzili, Italy. This program will involve medicinal chemistry and molecular pharmacology efforts with analog synthesis and characterization in mGluR functional assays, in vitro characterization of their neuroprotective activities and early ADME-tox assessments.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In addition to robust neuroprotective activity, GDNF was already shown to exert motor improvements both in pre-clinical models and in the clinic. However, due to its protein nature, its clinical use has been restricted. The possibility to orally enhance striatal GDNF level with small molecules would therefore be a real breakthrough in the treatment of Parkinson’s Disease.
Anticipated Outcome:
The stimulating role of mGluR3 activation on TGF-beta and GDNF production, together with clinical observation showing that group II mGluRs agonists are well tolerated, make this novel neuroprotective mechanism of action very promising. Candidates for in vivo studies selected by this program will be ~2 years from first tests in man.
Final Outcome
The first objective of the project was reached as a candidate for in vivo evaluations was nominated. This compound shows PAM activity below 100nM on mGluR3, very good selectivity profile against the other mGluR subtypes, including against the close mGluR2, no flag in early ADME-Tox evaluations and an excellent pharmacokinetic profile with high oral bioavailability and BBB penetration.
Compounds from this series of mGluR3 PAM also showed in vitro proofs of concept with neuroprotective activity on cortical and striatal primary neuron cultures challenged with NMDA. Moreover, these molecules were able to induce productions of neurotrophic factors such as GDNF and TGF-b. Interestingly, neuroprotective activity and effect on neurotrophic factor levels were similar to those obtained with the group II mGluR agonist LY379268.
Compounds identified in this program therefore represent optimized tools that can be used to the next level of characterization toward the demonstration of a neuroprotective role of mGluR3 PAM in in vivo PD models.