(±)-2-(N-tert-Butylamino)-3′-[ 125I]-iodo-4′- azidopropiophenone: A dopamine transporter and nicotinic acetylcholine receptor photoaffinity ligand based on bupropion (Wellbutrin, Zyban)

DOI

10.1016/j.bmcl.2011.10.086

Document Type

Journal Article

Publication Date

1-1-2012

Publication Title

Bioorganic and Medicinal Chemistry Letters

Volume

22

Issue

1

First Page

523

Last Page

526

ISSN

0960894X

Keywords

Bupropion, Dopamine transporter, Nicotinic acetylcholine receptor, Photoaffinity labeling

Abstract

Towards addressing the knowledge gap of how bupropion interacts with the dopamine transporter (DAT) and nicotinic acetylcholine receptors (nAChRs), a ligand was synthesized in which the chlorine of bupropion was isosterically replaced with an iodine and a photoreactive azide was added to the 4′-position of the aromatic ring. Analog (±)-3 (SADU-3-72) demonstrated modest DAT and α4β2 nAChR affinity. A radioiodinated version was shown to bind covalently to hDAT expressed in cultured cells and affinity-purified, lipid-reincorporated human α4β2 neuronal nAChRs. Co-incubation of (±)-[ 125I]-3 with non-radioactive (±)-bupropion or (-)-cocaine blocked labeling of these proteins. Compound (±)-[ 125I]-3 represents the first successful example of a DAT and nAChR photoaffinity ligand based on the bupropion scaffold. Such ligands are expected to assist in mapping bupropion-binding pockets within plasma membrane monoamine transporters and ligand-gated nAChR ion channels. © 2011 Elsevier Ltd. All rights reserved.

Open Access

Green Accepted

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