It has recently been shown that the specific activation of mGluR3 induced the production of neurotrophic factors such as GDNF and TGF�. Consequently, both in vitro and in vivo studies demonstrated that LY379268, a reference mGluR2/mGluR3 agonist, showed neuroprotection in Parkinson's disease preclinical models.GPCR allosteric modulators constitute a novel class of small molecule able to modulate the endogenous ligand activity on its receptor. They bring two main advantages in terms of drug discovery as compared with orthosteric ligands: a. an access to a more tractable chemistry for peptide, lipid and class C GPCRs. b. an easier access to subtype selective agents.At Domain Therapeutics, a novel family of submicromolar mGluR3 PAMs was discovered. These small molecules are heterocyclic derivatives showing no activity for the close mGluR2 subtype. Chemical optimization was performed using not only SAR on the receptor (compound dose-response or glutamate shift experiments) but also microsomal stability determination (HLM and RLM) and rapid in vivo B/P evaluation (p.o, rat) of a small set of compounds in order to identify potential candidates for in vivo evaluation in Parkinson's disease models.Moreover, some of these mGluR3 PAMs have been characterized in vitro in neuroprotection models using cultures from wild-type and mGluR3-KO mice and in neurotrophic factor production. Our results show that mGluR3 PAMs have similar in vitro activities as LY379268.

Discovery and optimization of selective mGluR3 PAMs towards novel neuroprotective agents for the treatment of Parkinson's disease

248th National Meeting (2014)

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