New GPR55 modulators bearing a 3-benzylquinolin-2(1H)-one scaffold: synthesis, evaluation of affinity/selectivity and assessment of neuroprotective action

GPR55 is a G-protein-coupled receptor highly expressed in the human central nervous system, particularly in neurons, astrocytes, and microglia. Although its precise physiological role remains under investigation, GPR55, which has been proposed as a putative third cannabinoid receptor, is increasingly recognized for its involvement in the regulation of neuroinflammatory processes and has emerged as a promising therapeutic target for neurodegenerative disorders, including Parkinson’s disease (PD).The aim of this PhD thesis was to design and synthesize novel GPR55 modulators to serve as biopharmacological tools for structure–activity relationship (SAR) studies and to identify selective and potent ligands. During my PhD, eight new series of 3-benzylquinolin-2(1H)-one derivatives were synthesized and thoroughly characterized. Selected compounds were evaluated for their binding affinity for GPR55 and for selectivity over the two classical cannabinoid receptors, CB1R and CB2R, using radioligand binding assays. Several derivatives exhibited improved affinity compared to previously reported compounds, with some showing selectivity over CB1R and CB2R receptors. Two derivatives were subsequently tested in an in vitro Parkinson’s disease model, and one of them demonstrated significant neuroprotective potential against toxin-induced neuronal damage. Overall, this work identifies novel, potent, and selective GPR55 ligands and highlights the therapeutic relevance of targeting GPR55 in neurodegenerative diseases associated with neuroinflammation.