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Characterization of Novel Pyrovalerone Analogs as Potential Dopamine Transporter Irreversible Ligands

The dopamine transporter (DAT), a member of the neurotransmitter:sodium symporter protein (NSS) family, is responsible for clearance of synaptic dopamine and represents a principal biological target for cocaine and other abused psychostimulants. DAT structure‐function studies have largely centered on the tropane‐based DAT blockers cocaine and benztropine. Non‐tropane DAT reuptake blockers such as pyrovalerone and methylphenidate have received less attention, yet appear to carry less abuse potential. To investigate the direct contacts between the DAT and non‐tropane ligands, analogs of pyrovalerone (a higher affinity structural variant of the antidepressant and smoking cessation agent bupropion) have been synthesized as potential irreversible DAT photoaffinity ligands. Binding affinity and dopamine uptake inhibition potency (DUIP) for these analogs were assessed via [3H]‐WIN‐35,428 displacement and [3H]‐dopamine uptake inhibition assays in hDAT N2A cells. 4′‐Azido‐3′‐iodo pyrovalerone retained high binding affinity (Ki=78nM) and moderate DUIP (IC50=264nM), representing a candidate photoaffinity probe. DAT molecular model docking of the ligand suggests that regions including the transmembrane 1 / extracellular loop 1 region are most likely to covalently ligate with the reactive nitrene atom in this photoaffinity probe. Our results demonstrate a multidisciplinary approach towards mapping the DAT residues involved in binding of non‐tropane DAT ligands.