Autophagy inducers for treatment of CNS conditions
Inventors
HE, Congcong • Huang, Sui • Wang, Chen • ROCCHI, Altea • Marugan, Juan Jose • Ferrer, Marc • Patnaik, Samarjit • CHEN, Yuchi • Frankowski, Kevin • Schoenen, Frank J.
Assignees
University of Kansas • Northwestern University • US Department of Health and Human Services
Publication Number
US-11241436-B2
Publication Date
2022-02-08
Expiration Date
2038-01-25
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Abstract
The invention provides a compound of formula (I): wherein R1, R2, R3, and R4 are as defined herein, ginsenoside Rg2 of structure (II): or a combination thereof, for use in treating or preventing a condition responsive to the induction of autophagy in a brain of a mammal in need thereof.
Core Innovation
The invention provides compounds, including a compound of formula (I), ginsenoside Rg2, and related ginsenosides; and methods of using these compounds for treating or preventing conditions responsive to the induction of autophagy in the brain of mammals in need thereof. It also provides pharmaceutical compositions comprising these compounds and methods of treating such conditions by administering effective amounts of the compounds.
The background identifies problems associated with long-term cannabinoid use, including rapid development of tolerance leading to diminished therapeutic effects and addiction concerns. Neurodegenerative diseases like Alzheimer's disease are characterized by protein aggregation, such as amyloid plaques and neurofibrillary tangles, with no effective cures and unclear mechanisms of disease progression. Thus, there is an unmet need for new therapies to treat neurodegenerative diseases and to address cannabinoid tolerance.
The invention solves these problems by identifying autophagy induction as a mechanism to maintain cannabinoid receptor 1 (CB1R) functionality and prevent cannabinoid tolerance. It demonstrates that compounds like ML246 and ginsenoside Rg2 induce autophagy, disrupt the Beclin 2-GASP1 interaction responsible for CB1R degradation, thereby preserving receptor levels and analgesic response. Additionally, genetic, pharmacological, and physiological methods of autophagy activation are shown to reduce amyloid beta (Aβ) accumulation and improve cognitive function in neurodegenerative disease models, providing new approaches for treatment and prevention.
Claims Coverage
The patent contains one independent method claim describing a method of treating a condition responsive to autophagy induction in the brain by administering a compound of formula (I). The claims outline inventive features related to compound structures, therapeutic effects on cannabinoid tolerance and neurodegenerative diseases, and specific receptor agonist interactions.
Method of treating conditions via administration of compounds of formula (I)
A method for treating a condition responsive to induction of autophagy in a mammalian brain by administering an effective amount of a compound of formula (I) comprising specific substituents as defined in the patent, including ginsenoside Rg2 and related compounds.
Reduction of cannabinoid tolerance and enhancement of analgesic effects
The method results in the reduction of cannabinoid tolerance and enhancement of cannabinoid analgesic effects, particularly in conditions involving CB1R receptor agonists such as cannabinoids, including tetrahydrocannabinol.
Treatment of Alzheimer's disease by autophagy induction
The method includes treatment of Alzheimer's disease wherein induction of autophagy results in reduction of amyloid β peptides, specifically Aβ42 peptide, contributing to neurodegenerative disease management.
Use of specific heterocyclylalkyl substituents in compounds
The compounds used in the method may include heterocyclylalkyl groups such as (tetrahydrofuran-3-yl)methyl, (tetrahydrofuran-2-yl)methyl, or (tetrahydro-2H-pyran-4-yl)methyl as substituents, contributing to the inventive chemical structure.
The claims collectively cover methods of treating autophagy-responsive brain conditions by administration of defined chemical compounds, highlighting autophagy induction to counteract cannabinoid tolerance, enhance analgesic effects, and treat neurodegenerative diseases such as Alzheimer's, with detailed chemical structures and specific receptor interactions.
Stated Advantages
Prevention and reduction of cannabinoid tolerance to maintain analgesic efficacy after repeated cannabinoid exposure.
Enhancement of cannabinoid receptor 1 (CB1R) signaling and functional receptor levels in the brain.
Pharmacological and physiological induction of autophagy provides neuroprotective effects and improves cognitive function in neurodegenerative disease models.
Use of brain-penetrable autophagy-inducing compounds offers a novel therapeutic strategy for treating neurodegenerative diseases and cannabinoid tolerance.
Documented Applications
Treatment of conditions responsive to autophagy induction in the brain, including prevention of cannabinoid tolerance and enhancement of analgesic effects of cannabinoids.
Treatment and prevention of neurodegenerative diseases such as Alzheimer's disease and Huntington's disease by reducing amyloid beta (Aβ) peptides and huntingtin protein via autophagy induction.
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