Beyond Single-Target Therapy: Dual-Acting Cannabinoid Type-2 Receptor Modulation in Neurological Disorders

Neurological disorders such as Alzheimer's disease, Parkinson's disease, and neuroinflammatory conditions involve complex, interconnected mechanisms, including neuroinflammation, oxidative stress, cholinergic dysfunction, and synaptic impairment. The cannabinoid type-2 receptor (CB2R), primarily expressed in immune and glial cells, has emerged as a promising therapeutic target due to its role in modulating neuroinflammation and providing neuroprotection without the psychoactive effects associated with CB1R activation. Recent research highlights the potential of dual-acting CB2R ligands that also modulate CB1R, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), offering a multitarget approach to neurological disorders. Although CB1R expression was identified in 1993, significant progress in designing receptor modulators began in the 2000s, with recent focus expanding to autoimmune, metabolic, and cancer-related applications. This review summarizes advances in the design, synthesis, and structure-activity relationships of CB2R-targeting ligands, emphasizing dual- or multitarget agents with cholinesterase inhibitory activity. Key chemical scaffolds include synthetic cannabinoids, heterocyclic compounds, and hybrid molecules integrating cholinesterase pharmacophores. Molecular docking and in silico studies are discussed to elucidate ligand-receptor interactions, binding modes, and determinants of selectivity. Overall, CB2R-centric dual-acting ligands represent a promising strategy for addressing multifactorial neurological disorders.