Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (卤)-threo-Methylphenidate
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- 作者：David J. Lapinsky ; Nageswari Yarravarapu ; Tammy L. Nolan ; Christopher K. Surratt ; John R. Lever ; Michael Tomlinson ; Roxanne A. Vaughan ; Howard M. Deutsch
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：May 10, 2012
- 年：2012
- 卷：3
- 期：5
- 页码：378-382
- 全文大小：225K
- 年卷期：v.3,no.5(May 10, 2012)
- ISSN：1948-5875
文摘
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 (卤)-threo-methylphenidate. (卤)-threo-4-Azido-3-iodomethylphenidate [(卤)-6; Ki = 4.0 卤 0.8 nM] displayed high affinity for hDAT. Moreover, a radioiodinated analogue of (卤)-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鈥揻unction studies.