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[摘要]：The development of photoaffinity ligands for determining covalent points of attachment to the dopamine transporter (DAT) has predominantly focused on tropane-based compounds bearing variable-length linkers between the photoreactive group and the inhibitor pharmacophore. To expand the array of photoprobes useful for mapping inhibitor-binding pockets within the DAT, a compact nontropane ligand was synthesized featuring a photoreactive azide and iodine tag directly attached to the aromatic ring of (+/-)-threo-methylphenidate. (+/-)-threo-4-Azido-3-iodomethylphenidate [(+/-)-6; K-i = 4.0 +/- 0.8 nM] displayed high affinity for hDAT. Moreover, a radioiodinated analogue of (+/-)-6 demonstrated covalent ligation to the DAT in cultured cells and rat striatal membranes, thus suggesting the potential utility of this photoprobe in DAT structure-function studies. |
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