Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.

Autor:	Warren HT; Department of Chemistry, University of California, Davis, Davis, California 95616, United States.; Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, California 95616, United States., Saeger HN; Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, California 95616, United States.; Pharmacology and Toxicology Graduate Group, University of California, Davis, Davis, California 95616, United States., Tombari RJ; Department of Chemistry, University of California, Davis, Davis, California 95616, United States., Chytil M; Delix Therapeutics, Inc., Bedford, Massachusetts 01730, United States., Rasmussen K; Delix Therapeutics, Inc., Bedford, Massachusetts 01730, United States., Olson DE; Department of Chemistry, University of California, Davis, Davis, California 95616, United States.; Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, California 95616, United States.; Center for Neuroscience, University of California, Davis, Davis, California 95618, United States.; Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California 95817, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 May 09; Vol. 67 (9), pp. 6922-6937. Date of Electronic Publication: 2024 Apr 22.
DOI:	10.1021/acs.jmedchem.3c01696
Abstrakt:	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.
Databáze:	MEDLINE
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