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

Hugo R. Arias, Dominik Feuerbach, Katarzyna M. Targowska-Duda, Shaili Aggarwal, David J. Lapinsky, Krzysztof Jozwiak

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The pharmacological properties of (±)-2-(N-tert-butylamino)- 3′-iodo-4′-azidopropiophenone [(±)-SADU-3-72], a photoreactive analog of bupropion (BP), were characterized at different muscle nicotinic acetylcholine receptors (AChRs) by functional and structural approaches. Ca2+ influx results indicate that (±)-SADU-3-72 is 17- and 6-fold more potent than BP in inhibiting human (h) embryonic (hα1β1γδ) and adult (hα1β1δ) muscle AChRs, respectively. (±)-SADU-3-72 binds with high affinity to the [ 3H]TCP site within the resting or desensitized Torpedo AChR ion channel, whereas BP has higher affinity for desensitized AChRs. Molecular docking results indicate that both SADU-3-72 enantiomers 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 (±)-SADU-3-72 may enhance its interaction with polar groups and the formation of hydrogen bonds at AChRs, thus supporting the observed higher potency and affinity of (±)-SADU-3-72 compared to BP. Collectively our results are consistent with a model where BP/SADU-3-72 and TCP bind to overlapping sites within the lumen of muscle AChR ion channels. Based on these results, we believe that (±)-SADU-3-72 is a promising photoprobe for mapping the BP binding site, especially within the resting AChR ion channel.

Original languageEnglish
Pages (from-to)1433-1441
Number of pages9
JournalNeurochemistry International
Volume61
Issue number8
DOIs
StatePublished - 1 Dec 2012
Externally publishedYes

Fingerprint

Bupropion
Nicotinic Receptors
Cholinergic Receptors
Ion Channels
Torpedo
Valine
Muscles
2-(N-tert-butylamino)-3'-iodo-4'-azidopropiophenone
Serine
Hydrogen
Binding Sites
Pharmacology

Keywords

  • Antidepressants
  • Bupropion
  • Conformational states
  • Nicotinic acetylcholine receptors
  • Noncompetitive antagonists
  • Photoreactive ligand

Cite this

Arias, Hugo R. ; Feuerbach, Dominik ; Targowska-Duda, Katarzyna M. ; Aggarwal, Shaili ; Lapinsky, David J. ; Jozwiak, Krzysztof. / Structural and functional interaction of (±)-2-(N-tert-butylamino)- 3′-iodo-4′-azidopropiophenone, a photoreactive bupropion derivative, with nicotinic acetylcholine receptors. In: Neurochemistry International. 2012 ; Vol. 61, No. 8. pp. 1433-1441.
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Structural and functional interaction of (±)-2-(N-tert-butylamino)- 3′-iodo-4′-azidopropiophenone, a photoreactive bupropion derivative, with nicotinic acetylcholine receptors. / Arias, Hugo R.; Feuerbach, Dominik; Targowska-Duda, Katarzyna M.; Aggarwal, Shaili; Lapinsky, David J.; Jozwiak, Krzysztof.

In: Neurochemistry International, Vol. 61, No. 8, 01.12.2012, p. 1433-1441.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structural and functional interaction of (±)-2-(N-tert-butylamino)- 3′-iodo-4′-azidopropiophenone, a photoreactive bupropion derivative, with nicotinic acetylcholine receptors

AU - Arias, Hugo R.

AU - Feuerbach, Dominik

AU - Targowska-Duda, Katarzyna M.

AU - Aggarwal, Shaili

AU - Lapinsky, David J.

AU - Jozwiak, Krzysztof

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Y1 - 2012/12/1

N2 - The pharmacological properties of (±)-2-(N-tert-butylamino)- 3′-iodo-4′-azidopropiophenone [(±)-SADU-3-72], a photoreactive analog of bupropion (BP), were characterized at different muscle nicotinic acetylcholine receptors (AChRs) by functional and structural approaches. Ca2+ influx results indicate that (±)-SADU-3-72 is 17- and 6-fold more potent than BP in inhibiting human (h) embryonic (hα1β1γδ) and adult (hα1β1δ) muscle AChRs, respectively. (±)-SADU-3-72 binds with high affinity to the [ 3H]TCP site within the resting or desensitized Torpedo AChR ion channel, whereas BP has higher affinity for desensitized AChRs. Molecular docking results indicate that both SADU-3-72 enantiomers 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 (±)-SADU-3-72 may enhance its interaction with polar groups and the formation of hydrogen bonds at AChRs, thus supporting the observed higher potency and affinity of (±)-SADU-3-72 compared to BP. Collectively our results are consistent with a model where BP/SADU-3-72 and TCP bind to overlapping sites within the lumen of muscle AChR ion channels. Based on these results, we believe that (±)-SADU-3-72 is a promising photoprobe for mapping the BP binding site, especially within the resting AChR ion channel.

AB - The pharmacological properties of (±)-2-(N-tert-butylamino)- 3′-iodo-4′-azidopropiophenone [(±)-SADU-3-72], a photoreactive analog of bupropion (BP), were characterized at different muscle nicotinic acetylcholine receptors (AChRs) by functional and structural approaches. Ca2+ influx results indicate that (±)-SADU-3-72 is 17- and 6-fold more potent than BP in inhibiting human (h) embryonic (hα1β1γδ) and adult (hα1β1δ) muscle AChRs, respectively. (±)-SADU-3-72 binds with high affinity to the [ 3H]TCP site within the resting or desensitized Torpedo AChR ion channel, whereas BP has higher affinity for desensitized AChRs. Molecular docking results indicate that both SADU-3-72 enantiomers 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 (±)-SADU-3-72 may enhance its interaction with polar groups and the formation of hydrogen bonds at AChRs, thus supporting the observed higher potency and affinity of (±)-SADU-3-72 compared to BP. Collectively our results are consistent with a model where BP/SADU-3-72 and TCP bind to overlapping sites within the lumen of muscle AChR ion channels. Based on these results, we believe that (±)-SADU-3-72 is a promising photoprobe for mapping the BP binding site, especially within the resting AChR ion channel.

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KW - Bupropion

KW - Conformational states

KW - Nicotinic acetylcholine receptors

KW - Noncompetitive antagonists

KW - Photoreactive ligand

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