Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets.

Brogan JT, Stoops SL, Lindsley CW
ACS Chem Neurosci. 2012 3 (9): 658-64

PMID: 23019492 · PMCID: PMC3447392 · DOI:10.1021/cn300064r

The synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloid, from the marine opisthobranch mollusk Phidiana militaris is reported. The synthesis proceeds in six steps from known indole acetic acids in 39.9% (phidianidine A) and 21% (phidianidine B) overall yields from commercially available materials. Biological characterization found that phidianidines A and B are selective inhibitors of DAT (versus SERT and NET) and a selective, potent ligand and partial agonist of the μ opioid receptor (versus δ- and κ-opioid receptors). Moreover, neither phidianidines A and B are cytotoxic, and thus represent an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries and prepared a diverse series of unnatural analogs.

MeSH Terms (21)

Animals Cell Proliferation Cell Survival Central Nervous System Agents CHO Cells Chromatography, High Pressure Liquid Cricetinae Cricetulus Dopamine Plasma Membrane Transport Proteins Gastropoda Guanosine 5'-O-(3-Thiotriphosphate) HEK293 Cells Humans Indicators and Reagents Indole Alkaloids Ligands Oxadiazoles Radioligand Assay Receptors, Opioid, mu Serotonin Plasma Membrane Transport Proteins Structure-Activity Relationship

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