Development of Delta Opioid Receptor Antagonists Which Prevent Alzheimer's Disease-Like Pathology in the 5X-Familial Alzheimer's Disease [5XFAD] Mouse Model.

Alzheimer's Disease is a growing health concern, with no available disease-modifying treatments. A previous report suggested that a Delta Opioid Receptor (DOR) antagonist could prevent Alzheimer's-like pathology; however, no DOR antagonists are clinically approved. We thus expanded on our previous structure-activity relationship work on morphinan scaffold DOR antagonists to generate and evaluate new DOR antagonist ligands. We identified a lead compound 12 (SRI-22136) with sub-nM DOR potency, high selectivity, and high inhibition of β-secretase activity. We further evaluated 12 in CD-1 mice, finding full antagonist efficacy at 1 mg/kg by the intraperitoneal route. We then tested the ability of 12 to prevent Alzheimer's-like pathology in a 5XFAD transgenic mouse model, with daily treatment from 2 to 5 months of age. This treatment completely prevented Alzheimer's-like pathology, including memory deficits, β-secretase activity, Aβ1-42 accumulation, and brain inflammatory markers. Together these results suggest 12 as a potential new lead compound to prevent Alzheimer's Disease.