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Identification of Psychoplastogenic Tropanes Lacking Muscarinic Activity
Hunter T Warren1,2, Winston L Chow1,2, Milan Chytil3
1Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States.
Journal of Medicinal Chemistry
|July 9, 2024
Summary
Researchers developed novel tropane compounds that promote neuroplasticity without the side effects of scopolamine. These new psychoplastogens enhance cortical neuronal growth while reducing unwanted muscarinic receptor activity.
Area of Science:
- Neuroscience
- Pharmacology
- Medicinal Chemistry
Background:
- Tropane-containing small molecules, such as scopolamine, show promise as psychoplastogens.
- However, their broad antagonism of muscarinic receptor subtypes can lead to anticholinergic side effects.
- Developing psychoplastogens with a reduced side effect profile is a significant therapeutic goal.
Purpose of the Study:
- To identify novel tropane derivatives that retain neuroplasticity-promoting effects.
- To decouple the psychoplastogenic activity from muscarinic receptor antagonism.
- To discover compounds with reduced anticholinergic side effects compared to scopolamine.
Main Methods:
- Phenotypic structure-activity relationship (SAR) studies were conducted.
- Structurally diverse subclasses of tropanes were synthesized and evaluated.
- Assays were performed to measure cortical neuronal growth and muscarinic receptor activity.
Main Results:
- Several novel tropane compounds were discovered.
- These compounds significantly increased cortical neuronal growth.
- The novel tropanes exhibited drastically reduced activity at all muscarinic receptor subtypes compared to scopolamine.
Conclusions:
- Novel tropane derivatives offer a promising avenue for psychoplastogen development.
- Decoupling neuroplasticity from muscarinic activity is achievable.
- These findings pave the way for safer psychoplastogenic therapeutics with fewer side effects.
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