Abstract
Natural products have a long history as a source of psychoactive agents and pharmacological tools for understanding the brain and its circuitry. In the last two decades, marine cyanobacteria have become a standard source of natural product ligands with cytotoxic properties. The study of cyanobacterial metabolites as CNS modulatory agents has remained largely untapped, despite the need for new molecules to treat and understand CNS disorders. We have generated a library of 301 fractions from 37 field collected cyanobacterial samples and screened these fractions against a panel of CNS receptors using radiolabeled ligand competitive-binding assays. Herein we present an analysis of the screening data collected to date, which show that cyanobacteria are prolific producers of compounds which bind to important CNS receptors, including those for 5-HT, DA, monoamine transporters, adrenergic, sigma, and cannabinoid receptors. In addition to the analysis of our screening efforts, we will also present the isolation of five compounds from the same cyanobacterial collection to illustrate how pre-fractionation followed by radioligand screening can lead to rapid identification of selective CNS agents. The systematic screening of natural products sources, specifically filamentous marine cyanobacteria, will yield a number of lead compounds for further development as pharmacological tools and therapeutics.
Highlights
Since the 1970s [1,2], marine cyanobacteria have been studied as a source for novel bioactive natural products
The high degree of chemical diversity among cyanobacterial natural products is attributed to their complex biosynthetic machinery and relatively large genomes that integrates important secondary metabolite pathways with polyketide synthases (PKS) and nonribosomal peptide synthases (NRPS)
While testing only the crude extracts would have resulted in 63% of cyanobacterial samples samples demonstrating some type of biological activity, when the extracts are pre-fractionated, the demonstrating some type of biological activity, when the extracts are pre-fractionated, the percent of percent of active fractions increases to 72%
Summary
Since the 1970s [1,2], marine cyanobacteria have been studied as a source for novel bioactive natural products. Due to some limitations, such as difficulty of collection, inadequate sample sizes, or general toxicity of some extracts, the biological diversity of marine ecosystems has not been widely studied as a source of modulators of G-protein coupled receptors (GPCRs) and the central nervous system (CNS). 2 2ofof a broad GPCR screen we believe additional leads can be discovered but hits must be followed up a broad. GPCR screen weand believe additional leads can be discovered but hitsand must be followed up with with additional in vitro in vivo assays examining specificity, efficacy, toxicity. 5-HTRs, MATs, and CNS receptors using the NIMH Psychoactive Drug Screening Program (PDSP) [16].
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