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 language | English |
|---|---|
| Pages (from-to) | 1433-1441 |
| Number of pages | 9 |
| Journal | Neurochemistry International |
| Volume | 61 |
| Issue number | 8 |
| DOIs | |
| State | Published - 1 Dec 2012 |
| Externally published | Yes |
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Keywords
- Antidepressants
- Bupropion
- Conformational states
- Nicotinic acetylcholine receptors
- Noncompetitive antagonists
- Photoreactive ligand
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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 journal › Article
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
PY - 2012/12/1
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.
KW - Antidepressants
KW - Bupropion
KW - Conformational states
KW - Nicotinic acetylcholine receptors
KW - Noncompetitive antagonists
KW - Photoreactive ligand
UR - http://www.scopus.com/inward/record.url?scp=84870299499&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2012.10.011
DO - 10.1016/j.neuint.2012.10.011
M3 - Article
C2 - 23103524
AN - SCOPUS:84870299499
VL - 61
SP - 1433
EP - 1441
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
IS - 8
ER -