Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer’s Disease

Tauopathy, neuronal atrophy, and psychological impairments
are
hallmarks of neurodegenerative diseases, such as Alzheimer’s
disease, that currently lack efficacious clinical treatments capable
of rectifying these issues. To address these unmet needs, we used
rational drug design to combine the pharmacophores of DYRK1A inhibitors
and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using
this approach, we discovered a nonhallucinogenic compound capable
of promoting cortical neuron growth and suppressing tau hyperphosphorylation
while also having the potential to mitigate the biological and psychological
symptoms of dementia. Together, our results suggest that hybridization
of the DYRK1A and psychoplastogen pharmacophores represents a promising
strategy for identifying compounds that might address the cognitive
as well as the behavioral and psychological symptoms of dementia.