Preclinical Evaluation of Marine Natural Products for Neuroscience Drug Discovery

Marine organisms produce a wide variety of primary and secondary metabolites with unique scaffolds that are biologically active. Manzamines are marine-derived polycyclic alkaloids. Approximately 100 manzamine-type alkaloids have been isolated from 16 marine sponge species, and some of these compounds are reported to have anti-inflammatory and neuritogenic properties. The goal of this study was to screen a subset of the manzamine compounds to identify novel neuroactive marine natural products for potential neuroscience drug development.  Calcium activity plays an important role in neurite outgrowth and connectivity, so we screened using FLIPR high-throughput assays. Minimal effects were observed on frequency and amplitude of calcium oscillations at 10 micromolar concentration, suggesting the manzamines do not directly modulate ion channels. Initial neurite outgrowth screens identified seven of the 21 compounds evaluated as potentially neuritogenic, based on total neurite outgrowth and complexity. Neurite outgrowth assays identified the following compounds for further analyses: manzamine A, 8-methoxymanzamine A, 12-propoxymanzamine A, 12-isobutoxymanzamine A, ATL 2-97, ircinin-1, and palinurin. Currently, we are assessing dose-response curves in neurite outgrowth assays for these compounds. Future directions include live-dead assays with propidium iodide and fluorescein diacetate using a dose-response curve to assess for neurotoxicity, and further analysis on potential pathways that may be contributing to neuritogenesis. Together, these studies will help identify novel neuroactive manzamine compounds for the marine natural products preclinical pipeline.

Learning Objectives:

1. Describe the drug development process and timeline.

2. Identify challenges associated with neuropharmacological drug development. 

3. Discuss how the marine environment contributes to unique metabolite structure.

4. Discuss upcoming marine natural products in preclinical and clinical use.