SRI 22136, A Novel Delta Opioid Receptor (DOR) Antagonist for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, which affects 47 million people worldwide. There are over five million AD patients over the age of 65 in the U.S. which is predicted to increase to 16 million by 2050. There are currently no approved disease-modifying therapies for AD and attempts to prevent or slow the progression of the formation of beta-amyloid plaques by targeting both the beta-secretase 1 (BACE1) and gamma-secretase enzymes have not yet achieved clinical success. Studies suggest that indirect modulation of the function of these enzymes via G-protein coupled receptors (GPCRs) may provide a novel strategy to reduce A-beta peptide production with potentially less side effects. Among GPCRs that influence amyloidogenesis, the delta opioid receptor (DOR), in particular, has been shown to play an important role in the trafficking and function of BACE1 and gamma-secretase and in the production of A-beta peptide. DOR activation increases BACE1 and gamma-secretase activity in vitro and in a mouse model of AD, and antagonism of DOR specifically blocks the amyloidogenic pathway and efficaciously prevents AD progression in mice. These effects were demonstrated using a known DOR antagonist, naltrindole. However, the potential of DOR antagonists as therapeutic agents for AD has yet to be explored. The aim of this project is to create novel DOR antagonists via medicinal chemistry and identify the most promising lead compound based on binding, selectivity, and functional profile in vitro. Further, select a small set of the most promising compounds and evaluate the compound's ability to mitigate AD-like pathology in vivo using APP/PS double-transgenic mice. We report here the identification of several selective DOR antagonists with low nanomolar affinity/potency that have been shown to block BACE1 activity in vitro. Lead compound SRI-22136, showed systemic stability and blood brain barrier penetration using the in vivo tail flick assay in CD-1 mice. SRI-22136 also showed efficacy in Novel Object Recognition (NOR) behavioral studies and in brain histological analysis studies we observed greater reduction in the AD pathological markers at a dose of 1mg/kg twice daily for 90 days continuous treatment in vivo using the APP/PS AD model double-transgenic mice. Also, in our brain histological analysis the compound exhibited greater efficacy in reduction of the AD pathology markers such as Aβ signal, and secondary inflammation and activated glia detected by GFAP (astrocytes) and CD11b (microglia) in APP/PS AD model double-transgenic mice. We further report our progress in testing this compound's effect on biochemical marker evaluation using the cortex and hippocampus regions of the APP/PS AD model double-transgenic mice.