A Tetrahydro-isoquinoline derivative as a novel mGlu2/3 Ago/PAM with therapeutic potential in models of Parkinsonism

Parkinson’s Disease (PD) is a neurodegenerative disorder marked by the progressive loss of dopaminergic neurons within the dopamine nigrostriatal pathway. Current pharmacological treatments provide only symptomatic relief and are associated with several adverse effects. While indirect evidence strongly supports the therapeutic potential of metabotropic glutamate receptor 3 (mGlu3) in PD, pharmacological limitations have hindered the progress of research in the field. In this study, we present the first functional characterization of a tetrahydroisoquinoline derivative acting as a dual agonist/positive allosteric modulator (Ago/PAM) of mGlu2/3. This compound exhibits slightly higher potency for mGlu3 compared to mGlu2, along with notable neurotrophic properties. The study employed complementary in vitro and in vivo approaches, using cellular model of PD and healthy male C57BL/6 mice. The novel Ago/PAM shows equal affinity for mGlu2 and mGlu3 and greater efficacy at mGlu3 receptors in recombinant cells. Exposure to the mGlu2/3 Ago/PAM protects the human neuroblastoma cell line SH-SY5Y from 6-hydroxydopamine (6-OHDA)-induced cell death by modulating neurotrophic signaling pathways, including the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) and Phosphatidylinositol 3-Kinase (PI3K)-AKT pathways. Moreover, this treatment increases the expression of Glial cell line-derived neurotrophic factor (GDNF), a key factor for dopaminergic neuron survival. Interestingly, pre-treatment with ML 337, a negative allosteric modulator for mGlu3, abolishes mGlu2/3 Ago/PAM-induced neuroprotective effects. In vivo administration of mGlu2/3 Ago/PAM upregulates GDNF and Brain derived neurotrophic factor (BDNF) expression, while activating MAPK/ERK and PI3K-AKT pathways in mouse brain regions involved in PD pathophysiology, such as the striatum, the hippocampus, and the prefrontal cortex. Collectively, these findings identify this tetrahydroisoquinoline-derived compound as a novel mGlu2/3 Ago/PAM with preferential activity at mGlu3, and provide its first functional characterization, demonstrating robust neurotrophic and neuroprotective effects. By combining agonist and positive allosteric modulation with mGlu3 selectivity, this compound represents a translationally promising strategy to counteract neurodegeneration and restore neuronal–glial homeostasis in PD. These results, though preliminary, support the therapeutic potential of this compound, and more broadly of mGlu3-targeted approaches, laying the foundation for future in vivo studies to validate efficacy, safety, and receptor specificity.