# Design, Synthesis, and Evaluation of Neural Plasticity-Promoting Analogs of Iboga and Ergoline Alkaloids

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $278,056

## Abstract

PROJECT SUMMARY/ABSTRACT
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.

## Key facts

- **NIH application ID:** 10406167
- **Project number:** 5R01GM128997-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** David E Olson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $278,056
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406167

## Citation

> US National Institutes of Health, RePORTER application 10406167, Design, Synthesis, and Evaluation of Neural Plasticity-Promoting Analogs of Iboga and Ergoline Alkaloids (5R01GM128997-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10406167. Licensed CC0.

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