147 | Screening of novel metabotropic glutamate receptor 4-oriented molecules in an in vitro model of Parkinson’s disease

Cristina Giuffré¹, Miriana Scordino¹, Giulia Urone¹, Miriam Buttacavoli¹, Alessandra Montalbano², Marilia Barreca², Roberta Bivacqua², Paola Barraja², Virginia Spano’², Giuseppa Mudo’¹, Valentina Di Liberto¹ | ¹Department of Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, Palermo, Italy; ²Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.

Abstract

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction. Its complex pathophysiology – characterized by oxidative stress and neuroinflammation – currently lacks a cure. Existing treatments are mainly symptomatic, emphasizing the need for disease-modifying therapies. Growing evidence supports the metabotropic glutamate receptor 4 (mGluR4) as a promising therapeutic target. Based on a tricyclic scaffold already reported in the literature, we synthesized a series of compounds with unique chemical decorations, aiming to develop new positive allosteric modulators (PAMs) of mGluR4. Using SH-SY5Y neuroblastoma cells, we first assessed cytotoxicity via dose-response analysis. Cells were then exposed to 6-hydroxydopamine (6-OHDA) to model PD in vitro and evaluate neuroprotective effects. The screening of a series of compounds featuring diverse chemical decorations enabled us to explore structure-function relationships. Notably, we observed distinct pharmacological profiles at the same doses, with varying degrees of neuroprotective activity depending on the nature of the functional groups introduced. These insights guided the identification of a lead compound with selectivity for mGluR4, a favorable safety profile, and promising neuroprotective properties – representing a valuable step toward the development of multitarget therapies for PD.