Evolution of a compact photoprobe for the dopamine transporter based on (±)-threo-methylphenidate

David J. Lapinsky; Nageswari Yarravarapu; Tammy L. Nolan; Christopher K. Surratt; John R. Lever; Michael Tomlinson; Roxanne A. Vaughan; Howard M. Deutsch

doi:10.1021/ml3000098

Evolution of a compact photoprobe for the dopamine transporter based on (±)-threo-methylphenidate

David J. Lapinsky, Nageswari Yarravarapu, Tammy L. Nolan, Christopher K. Surratt, John R. Lever, Michael Tomlinson, Roxanne A. Vaughan, Howard M. Deutsch

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	378-382
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	5
DOIs	https://doi.org/10.1021/ml3000098
State	Published - May 10 2012
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml3000098

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title = "Evolution of a compact photoprobe for the dopamine transporter based on (±)-threo-methylphenidate",

abstract = "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; Ki = 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.",

author = "Lapinsky, {David J.} and Nageswari Yarravarapu and Nolan, {Tammy L.} and Surratt, {Christopher K.} and Lever, {John R.} and Michael Tomlinson and Vaughan, {Roxanne A.} and Deutsch, {Howard M.}",

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AU - Lapinsky, David J.

AU - Yarravarapu, Nageswari

AU - Nolan, Tammy L.

AU - Surratt, Christopher K.

AU - Lever, John R.

AU - Tomlinson, Michael

AU - Vaughan, Roxanne A.

AU - Deutsch, Howard M.

PY - 2012/5/10

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Evolution of a compact photoprobe for the dopamine transporter based on (±)-threo-methylphenidate

Abstract

ASJC Scopus subject areas

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