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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish
Pages (from-to)2420-2430
Number of pages11
JournalInternational Journal of Biochemistry and Cell Biology
Volume45
Issue number11
DOIs
StatePublished - 11 Sep 2013
Externally publishedYes

Fingerprint

Quinuclidines
Nicotinic Receptors
Ion Channels
Binding Sites
Derivatives
Imipramine
Valine
Molecular Dynamics Simulation
Serine
Molecular dynamics
Cations
Assays
Salts
Cells
Pharmacology
Computer simulation
Experiments

Keywords

  • Competitive antagonists
  • Nicotinic acetylcholine receptors
  • Noncompetitive antagonists
  • Quinuclidines
  • Structure-activity relationship

Cite this

Arias, Hugo R. ; López, Jhon J. ; Feuerbach, Dominik ; Fierro, Angélica ; Ortells, Marcelo O. ; Pérez, Edwin G. / Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms. In: International Journal of Biochemistry and Cell Biology. 2013 ; Vol. 45, No. 11. pp. 2420-2430.
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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 journalArticle

TY - JOUR

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AU - Arias, Hugo R.

AU - López, Jhon J.

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AU - Fierro, Angélica

AU - Ortells, Marcelo O.

AU - Pérez, Edwin G.

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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.

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