Parkinson's Disease (PD) is a long-term neurodegenerative brain disorder that mainly
affects the motor system. The causes are still unknown, and even though currently there is no cure,
several therapeutic options are available to manage its symptoms. The development of novel antiparkinsonian
agents and an understanding of their proper and optimal use are, indeed, highly demanding.
For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been
the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD.
However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena)
associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian
efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt
to counteract the motor side effects associated with dopamine replacement therapy. Being one of
the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a
relevant target for drug discovery focused on a wide range of therapeutic areas, including Central
Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD,
excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives
for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses,
including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors,
metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of
PD and the importance of structure- and ligand-based in silico approaches for the development of
small molecules to target these receptors.