A TETRAHYDRO-ISOQUINOLINE DERIVATIVE AS A NOVEL mGlu2/3 AGO/PAM WITH THERAPEUTIC POTENTIAL IN EXPERIMENTAL MODELS OF PARKINSONISM

Parkinson’s disease (PD) is a complex and multi-factorial neurodegenerative disorder marked by the loss of dopaminergic neurons in the nigrostriatal circuit, with the progressive development of motor and non-motor symptoms. Currently, the gold-standard within the available drug therapies are dopamine-based therapies, which only help to mitigate symptoms and are also associated with several side-effects. Indeed, no disease-modifying pharmacological treatments have been available so far. In this context, indirect evidence has suggested that activation of the metabotropic Glutamate receptor 3 (mGlu3) exerts neuroprotective effects in animal models of PD, but, however, the lack of selective agonists for this receptor has hindered more in-depth investigations. Based on this background, the present study characterized, for the first time, a tetrahydro-isoquinoline derivative as an agonist/positive allosteric modulator (Ago/PAM) for the mGlu2/3, demonstrating its neuroprotective properties in a cellular model of PD and its neurotrophic effects in healthy mice. Despite showing equal affinity for mGlu2 and mGlu3, the novel Ago/PAM displays greater efficacy at mGlu3 receptors in recombinant cells. It protects the human neuroblastoma cell line SH-SY5Y against death induced by 6-hydroxydopamine (6- OHDA), a drug widely used to induce dopaminergic degeneration, involving the modulation of survival signaling pathways, such as the mitogen-activated protein kinases/extracellular signal- regulated kinase (MAPK/ERK) and the phosphatidylinositol 3-kinase (PI3K)–AKT pathways, together with the regulation of glial-derived neurotrophic factor (GDNF). Interestingly, the observed neuroprotection is lost in the presence of ML 337, a selective negative allosteric modulator (NAM) for mGlu3, suggesting the key role played by this mGluRs subtype. Moreover, in vivo treatment with the new mGlu2/3 Ago/PAM up-regulates the expression of GDNF and brain- derived neurotrophic factor (BDNF) and modulates the activation of MAPK/ERK and PI3K–AKT pathways in mouse brain regions potentially involved in PD pathophysiology. Overall, though preliminary, our results provide new insights into mGlu3 specific function and suggest the therapeutic potential of the new mGlu2/3 Ago/PAM in the management of PD.