Targeting neuroinflammation in Parkinson’s disease: an integrative review of rational design and molecular strategies for CB2 Selective Agonists

Parkinson’s disease (PD) is characterized by progressive dopaminergic degeneration and chronic neuroinflammation. The cannabinoid type 2 receptor (CB2R) has emerged as a promising therapeutic target due to its immunomodulatory effects without the psychotropic activity associated with CB1. This integrative review summarizes advances in the rational design, computational modeling, and preclinical evaluation of selective CB2 agonists for neuroprotection in PD. Following PRISMA 2020 guidelines, studies published between 2000 and 2025 were screened across major scientific databases. Thirty-eight articles met the inclusion criteria, comprising computational analyses and in vivo preclinical models. Evidence consistently shows that CB2 activation reduces microglial-driven neuroinflammation, oxidative stress, and dopaminergic loss. Progress in structure-based drug design, molecular docking, QSAR models, and cryo-EM data has guided the development of ligands with improved selectivity, affinity, and pharmacokinetic profiles. Despite the significant potential, clinical translation remains limited. Emerging strategies, including natural-product-based scaffolds, artificial intelligence workflows and allosteric modulation, represent promising directions for the next generation of CB2-targeted therapies.