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

Bindra S.; Rangarajan T.; Parambi D.; Kumar S.; Anal J.; Mathew B. · ChemMedChem · 2026

**Background & Methods** This is a narrative review examining dual-acting cannabinoid type-2 receptor (CB2R) ligands and their therapeutic potential in neurological disorders. The review synthesizes recent literature on CB2R modulation, structure-activity relationships, and multitarget drug design strategies combining CB2R activity with cholinesterase inhibition, incorporating molecular docking and in silico analyses to elucidate receptor-ligand interactions. **Key Findings** • CB2R represents a promising therapeutic target for neurological disorders including Alzheimer's disease, Parkinson's disease, and neuroinflammatory conditions, offering neuroprotection and neuroinflammation modulation without CB1R-associated psychoactive effects. • Dual- or multitarget CB2R ligands that simultaneously inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) while potentially modulating CB1R address interconnected disease mechanisms including neuroinflammation, oxidative stress, cholinergic dysfunction, and synaptic impairment. • Key chemical scaffolds for CB2R-targeting agents include synthetic cannabinoids, heterocyclic compounds, and hybrid molecules integrating cholinesterase pharmacophores, with molecular docking studies informing ligand design and selectivity determinants. **Dosage & Administration** Not reported. This review does not present clinical trials with specific dosing regimens or administration routes for CB2R-targeting compounds. **Safety & Adverse Effects** Not reported. The review emphasizes CB2R's lack of psychoactive effects compared to CB1R activation but does not discuss specific adverse effects or safety profiles of candidate compounds in clinical or preclinical studies. **Evidence Quality** This is a narrative review with inherent limitations in evidence strength. The review synthesizes literature on emerging drug design strategies and molecular mechanisms rather than presenting original experimental data or clinical trial results. As a 2026 publication examining an evolving field, it reflects recent advances in structure-activity relationship studies and computational modeling but lacks randomized controlled trial evidence or human safety/efficacy data. The multitarget approach is theoretically promising based on pathophysiological understanding but requires validation through preclinical and clinical studies. The review's value lies in synthesizing current knowledge on CB2R-targeting strategies and highlighting research directions rather than providing definitive clinical evidence for therapeutic application in neurological disorders.

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