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Bupropion inhibits human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Arias, H R and Feuerbach, Dominik and Ortells, M (2018) Bupropion inhibits human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. Neurotransmitter.

Abstract

The interaction of (±)-bupropion [(±)-BP] with the human (h) α3β4 nicotinic acetylcholine receptor (AChR) was determined by functional and structural approaches. The Ca2+ influx results indicated that (±)-BP inhibits hα3β4 AChRs with ~2-fold lower potency than that for its photoreactive analog (±)-2-(N-tert-butylamino)-3’-iodo-4’-azidopropiophenone [(±)-SADU-3-72], indicating that this compound can be used to further characterize the (±)-BP binding sites. The competition binding results showed that (±)-BP binds to the [3H]imipramine sites at desensitized hα3β4 AChRs with ~4-fold higher affinity compared to the resting state. Molecular docking results indicated that both enantiomers of BP and SADU-3-72, in the protonated state, interact with luminal and non-luminal sites. BP interacts with a luminal site which overlaps with that for imipramine, and with non-luminal sites located in the transmembrane domain (TMD) at interfacial (+α3/-β4) and α3 intrasubunit sites, in the extracellular domain (ECD), and in the TMD-ECD junction at the +β4/-α3 and +β4/-β4 interfaces and within each subunit. Our results are consistent with a hα3β4 model where BP and SADU-3-72 bind to overlapping non-luminal sites as well as to non-overlapping luminal sites.

Item Type: Article
Date Deposited: 11 May 2018 00:45
Last Modified: 11 May 2018 00:45
URI: https://oak.novartis.com/id/eprint/32726

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