Abstract
This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6′) and valine (position 13′) rings that overlaps the imipramine binding site.
| Original language | English |
|---|---|
| Pages (from-to) | 2420-2430 |
| Number of pages | 11 |
| Journal | International Journal of Biochemistry and Cell Biology |
| Volume | 45 |
| Issue number | 11 |
| DOIs | |
| State | Published - 11 Sep 2013 |
| Externally published | Yes |
Fingerprint
Keywords
- Competitive antagonists
- Nicotinic acetylcholine receptors
- Noncompetitive antagonists
- Quinuclidines
- Structure-activity relationship
Cite this
}
Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms. / Arias, Hugo R.; López, Jhon J.; Feuerbach, Dominik; Fierro, Angélica; Ortells, Marcelo O.; Pérez, Edwin G.
In: International Journal of Biochemistry and Cell Biology, Vol. 45, No. 11, 11.09.2013, p. 2420-2430.Research output: Contribution to journal › Article
TY - JOUR
T1 - Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms
AU - Arias, Hugo R.
AU - López, Jhon J.
AU - Feuerbach, Dominik
AU - Fierro, Angélica
AU - Ortells, Marcelo O.
AU - Pérez, Edwin G.
PY - 2013/9/11
Y1 - 2013/9/11
N2 - This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6′) and valine (position 13′) rings that overlaps the imipramine binding site.
AB - This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca2+ influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6′) and valine (position 13′) rings that overlaps the imipramine binding site.
KW - Competitive antagonists
KW - Nicotinic acetylcholine receptors
KW - Noncompetitive antagonists
KW - Quinuclidines
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84883500634&partnerID=8YFLogxK
U2 - 10.1016/j.biocel.2013.08.003
DO - 10.1016/j.biocel.2013.08.003
M3 - Article
C2 - 23954208
AN - SCOPUS:84883500634
VL - 45
SP - 2420
EP - 2430
JO - International Journal of Biochemistry and Cell Biology
JF - International Journal of Biochemistry and Cell Biology
SN - 1357-2725
IS - 11
ER -