A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex plays a key role in the pathophysiology of neuropsychiatric diseases such as depression, anxiety disorders, and addiction. These structural changes, such as the retraction of neurites and loss of dendritic spines, can potentially be counteracted by compounds capable of facilitating structural and functional neural plasticity. In fact, the promotion of neural plasticity in the prefrontal cortex has been proposed to play a crucial role in the therapeutic mechanism of fast-acting antidepressants and anxiolytics such as ketamine. Compounds from the iboga and ergoline families of natural products have shown enormous potential for promoting neuritogenesis, spinogenesis, and synaptogenesis in cortical neurons, and have demonstrated plasticity-promoting properties superior to ketamine. However, it is currently unknown which structural features of these molecules contribute to their efficacy. Our overall objective is to produce more effective and safer plasticity-promoting molecules through structure-activity relationship studies of these key scaffolds. To gain access to the large number of structural variants required for these studies, we propose novel synthetic routes to both the iboga and ergoline classes of natural products. The strategies we advance are significantly shorter than previously reported syntheses and allow for facile diversification and analog generation. The compounds that we design and synthesize will be assessed using novel in vitro neural plasticity assays developed in our lab. Ultimately, the work described here will fill the gap in our knowledge about how molecular structure impacts neural plasticity and will prove instrumental to the evolution of next-generation neurotherapeutics.

Public Health Relevance

Compounds capable of promoting neural plasticity, such as the fast-acting antidepressant ketamine, have enormous potential for treating neuropsychiatric disorders such as depression, anxiety, and addiction. However, it is currently unknown which structural features of these compounds are responsible for their beneficial effects on plasticity. The research described here explores synthetic strategies for accessing two important classes of natural products known to potently promote plasticity in order to understand what structural features are critical for their efficacy, and ultimately, to develop more effective and safer alternatives.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM128997-01
Application #
9576192
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2018-08-01
Project End
2023-05-31
Budget Start
2018-08-01
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Olson, David E (2018) Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. J Exp Neurosci 12:1179069518800508