title: Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets.
abstract: 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.
authors.affiliation: Departments of Pharmacology and Chemistry, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Brogan
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Stoops
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D049851:Gastropoda; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007202:Indicators and Reagents; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000819:agonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D002491:Central Nervous System Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D007202:Indicators and Reagents; D026121:Indole Alkaloids; D008024:Ligands; D010069:Oxadiazoles; D017450:Receptors, Opioid, mu; D050486:Serotonin Plasma Membrane Transport Proteins; C559224:phidianidine A; C559225:phidianidine B; D016244:Guanosine 5'-O-(3-Thiotriphosphate)