Abstract
We report the synthesis, binding kinetics, optical spectroscopy and predicted binding modes of a series of sterically demanding, fluorescent norepinephrine transporter (NET) ligands. A series of bulky stilbazolium dyes, including six newly synthesized compounds, were evaluated to determine the effect of extending the molecular probes' 'heads' or 'tails'. Taking advantage of the dyes' characteristic 'turn-on' emission, the kinetic binding parameters, kon and koff were determined revealing that extension of the molecules' tails is well tolerated while expansion of the head is not. Additionally, a 'headfirst' orientation appears to be preferred over a 'tail-first' binding pose. Further details of the possible binding modes were obtained from the emission spectra of the bound probes. A small range of interplanar twist angles, approximately 35° to 60°, is predicted to produce the observed emission. Docking experiments and molecular modelling support the kinetic and spectroscopic data providing structural insights into substrate binding.
| Original language | English |
|---|---|
| Pages (from-to) | 8710-8719 |
| Number of pages | 10 |
| Journal | Organic and Biomolecular Chemistry |
| Volume | 10 |
| Issue number | 43 |
| DOIs | |
| State | Published - Nov 21 2012 |
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ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Organic Chemistry
- Biochemistry
Cite this
Fluorescent stilbazolium dyes as probes of the norepinephrine transporter : Structural insights into substrate binding. / Wilson, James N; Brown, Adrienne S.; Babinchak, W. Michael; Ridge, Clark D.; Walls, Jamie.
In: Organic and Biomolecular Chemistry, Vol. 10, No. 43, 21.11.2012, p. 8710-8719.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fluorescent stilbazolium dyes as probes of the norepinephrine transporter
T2 - Structural insights into substrate binding
AU - Wilson, James N
AU - Brown, Adrienne S.
AU - Babinchak, W. Michael
AU - Ridge, Clark D.
AU - Walls, Jamie
PY - 2012/11/21
Y1 - 2012/11/21
N2 - We report the synthesis, binding kinetics, optical spectroscopy and predicted binding modes of a series of sterically demanding, fluorescent norepinephrine transporter (NET) ligands. A series of bulky stilbazolium dyes, including six newly synthesized compounds, were evaluated to determine the effect of extending the molecular probes' 'heads' or 'tails'. Taking advantage of the dyes' characteristic 'turn-on' emission, the kinetic binding parameters, kon and koff were determined revealing that extension of the molecules' tails is well tolerated while expansion of the head is not. Additionally, a 'headfirst' orientation appears to be preferred over a 'tail-first' binding pose. Further details of the possible binding modes were obtained from the emission spectra of the bound probes. A small range of interplanar twist angles, approximately 35° to 60°, is predicted to produce the observed emission. Docking experiments and molecular modelling support the kinetic and spectroscopic data providing structural insights into substrate binding.
AB - We report the synthesis, binding kinetics, optical spectroscopy and predicted binding modes of a series of sterically demanding, fluorescent norepinephrine transporter (NET) ligands. A series of bulky stilbazolium dyes, including six newly synthesized compounds, were evaluated to determine the effect of extending the molecular probes' 'heads' or 'tails'. Taking advantage of the dyes' characteristic 'turn-on' emission, the kinetic binding parameters, kon and koff were determined revealing that extension of the molecules' tails is well tolerated while expansion of the head is not. Additionally, a 'headfirst' orientation appears to be preferred over a 'tail-first' binding pose. Further details of the possible binding modes were obtained from the emission spectra of the bound probes. A small range of interplanar twist angles, approximately 35° to 60°, is predicted to produce the observed emission. Docking experiments and molecular modelling support the kinetic and spectroscopic data providing structural insights into substrate binding.
UR - http://www.scopus.com/inward/record.url?scp=84867496878&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867496878&partnerID=8YFLogxK
U2 - 10.1039/c2ob26633d
DO - 10.1039/c2ob26633d
M3 - Article
C2 - 23032519
AN - SCOPUS:84867496878
VL - 10
SP - 8710
EP - 8719
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
SN - 1477-0520
IS - 43
ER -