(±)-2-(N-tert-Butylamino)-3′-[125I]-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 (±)-[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.

Dextroamphetamine and Pramipexole Combination for Treatment-Resistant Unipolar Depression

“…5–10 A dopamine transporter photoaffinity ligand, (±)-2-(N-tert-Butylamino)-3′-[I-125]-iodo-4′-azidopropiophenone, had modest affinity with bupropion. 11 In the (I-123)IBZM single photon emission computed tomography study, atypical antipsychotic drugs, including 30 mg/day of aripiprazole, had no clinical benefit in patients with severe TRD despite their strong occupancy of dopamine 2 and 3 receptors. 12 An article describing how mesolimbic dopamine regulates motivated behavior was recently published.…”

Bupropion Binds to Two Sites in the Torpedo Nicotinic Acetylcholine Receptor Transmembrane Domain: A Photoaffinity Labeling Study with the Bupropion Analogue [125I]-SADU-3-72

“…[ 125 I]-SADU-3-72 (2057 Ci/mmol; Figure 1) was synthesized and radioiodinated according to the procedures outlined in (12). Torpedo californica electric organ was obtained from Aquatic Research Consultants (San Pedro, CA).…”

“…To this end, we recently developed a photoreactive analog of bupropion ([ 125 I]-SADU-3-72, Figure 1 (12)). that we use to identify and characterize the binding site(s) for bupropion in the Torpedo nAChR.…”

Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate

“…To date, the chemical development of DAT molecular probes has predominantly focused on phenyl- and benztropine-based tropane compounds, along with their conformationally flexible piperazine and piperidine analogs, whereas non-tropane probes have received significantly less attention. 2–4 Based on contrasting SAR between tropane and non-tropane DAT inhibitors, these ligand classes may be binding to different specific DAT sites or conformations, which may explain and even dictate their divergent subjective effects in psychostimulant abuse animal models. 5–8 In particular, the effect on DAT binding affinity by the substituents on the aromatic ring of (±)- threo -methylphenidate ((±)- 1 , Figure 1), a therapeutic non-tropane DAT inhibitor with low abuse potential, appears to be most similar to the so called “WIN” tropane compounds, wherein the aromatic phenyl ring is directly attached to the 3-position of the tropane ring system.…”

“…As a result, the development of irreversible molecular probes, such as affinity labels and photoaffinity ligands, remains an important research objective to understand the binding sites and conformational preferences of DAT inhibitors at the molecular level. To date, the chemical development of DAT molecular probes has predominantly focused on phenyl- and benztropine-based tropane compounds, along with their conformationally flexible piperazine and piperidine analogues, whereas nontropane probes have received significantly less attention. − On the basis of contrasting SAR between tropane and nontropane DAT inhibitors, these ligand classes may be binding to different specific DAT sites or conformations, which may explain and even dictate their divergent subjective effects in psychostimulant abuse animal models. − In particular, the effect on DAT binding affinity by the substituents on the aromatic ring of (±)- threo -methylphenidate [(±)- 1 , Figure ], a therapeutic nontropane DAT inhibitor with low abuse potential, appears to be most similar to the so-called “WIN” tropane compounds, wherein the aromatic phenyl ring is directly attached to the 3-position of the tropane ring system . In contrast to highly abused cocaine where the aromatic ring is attached to the tropane system via a 3β-ester, the effects of aromatic substituents on DAT affinity are quite different.…”