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Structural and functional interaction of (+)-2-(N-tert-butylamino)-3’-iodo-4’-azidopropiophenone, a photoactivatable bupropion derivative, with nicotinic acetylcholine receptors

Feuerbach, Dominik and Arias, Hugo R and Targowska-Duda, Katarzyna M and Aggarwal, Shaili and Lapinsky, Daniel J and Jozwiak, Krzysztof (2012) Structural and functional interaction of (+)-2-(N-tert-butylamino)-3’-iodo-4’-azidopropiophenone, a photoactivatable bupropion derivative, with nicotinic acetylcholine receptors. Biochemistry.

Abstract

The pharmacological properties of S-(+)-2-(N-tert-butylamino)-3’-iodo-4’-azidopropiophenone [(+)-SADU3-72], a photoactivatable analog of bupropion (BP), were characterized at different muscle nicotinic acetylcholine receptors (AChRs) by functional and structural approaches. Ca2+ influx results indicate that (+)-SADU3-72 is 17- and 6-fold more potent than BP in inhibiting human (h) embryonic (hα1β1γδ) and adult (hα1β1δ) muscle AChRs. (+)-SADU3-72 binds with high affinity to the [3H]TCP site at either the resting or desensitized Torpedo AChRs, whereas BP has higher affinity for the desensitized AChR. Molecular docking results indicate that both SADU3-72 isomers interact with the valine (position 13’) and serine (position 6’) rings. However, an additional domain, between the outer (position 20’) and valine rings, is observed in Torpedo AChR ion channels. Our results indicate that the azido group of (+)-SADU3-72 may enhance the interaction with polar groups as well as the formation of hydrogen bonds, supporting the observed higher potency and affinity of (+)-SADU3-72 compared to BP. Collectively these results are consistent with a model where BP/SADU3-72 and TCP bind to overlapping sites within the lumen of muscle AChR ion channels. Based on these results, we believe that (+)-SADU3-72 represents a promising photoprobe for mapping the BP binding site, especially within the resting AChR ion channel.

Item Type: Article
Keywords: Nicotinic acetylcholine receptors; Antidepressants; Bupropion; Photoactivatable probe; Noncompetitive antagonists; Conformational states
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/6131

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