| Updated in 6/16/2019 1:31:13 PM |
Viewed: 331 times |
(Journal Article) |
The international journal of biochemistry & cell biology 45 (11): 2420-30 (2013)
Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms.
Hugo R Arias
,
Jhon J López
,
Dominik Feuerbach
,
Angélica Fierro
,
Marcelo O Ortells
,
Edwin G Pérez
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 Ca(2+) 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.