title: (±)-2-(N-tert-Butylamino)-3'-[(125)I]-iodo-4'-azidopropiophenone: a dopamine transporter and nicotinic acetylcholine receptor photoaffinity ligand based on bupropion (Wellbutrin, Zyban).
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 (±)-[(125)I]-3 with non-radioactive (±)-bupropion or (-)-cocaine blocked labeling of these proteins. Compound (±)-[(125)I]-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.
authors: Division of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. lapinskyd@duq.edu
authors: David J
authors: DJ
authors: Lapinsky
authors: Shaili
authors: S
authors: Aggarwal
authors: Tammy L
authors: TL
authors: Nolan
authors: Christopher K
authors: CK
authors: Surratt
authors: John R
authors: JR
authors: Lever
authors: Rejwi
authors: R
authors: Acharya
authors: Roxanne A
authors: RA
authors: Vaughan
authors: Akash
authors: A
authors: Pandhare
authors: Michael P
authors: MP
authors: Blanton
mesh_terms: D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016642:Bupropion / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007455:Iodine / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D010777:Photochemistry / Q000379:methods; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: C572068:2-(N-tert-butylamino)-3'-iodo-4'-azidopropiophenone; D001386:Azides; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008024:Ligands; D011978:Receptors, Nicotinic; D016642:Bupropion; D007455:Iodine