Inhibitory mechanisms and binding site location for serotonin selective reuptake inhibitors on nicotinic acetylcholine receptors

Hugo R. Arias, Dominik Feuerbach, Pankaj Bhumireddy, Marcelo O. Ortells

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit hα1β1γδ AChR-induced Ca2+ influx with higher potencies than dizocilpine. The potency of fluoxetine is increased ∼10-fold after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-3H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits [3H]dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13′) and leucine (position 9′) rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20′, 21′, and 24′. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20′) rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization.

Original languageEnglish
Pages (from-to)712-724
Number of pages13
JournalInternational Journal of Biochemistry and Cell Biology
Volume42
Issue number5
DOIs
StatePublished - 1 May 2010
Externally publishedYes

Fingerprint

Fluoxetine
Serotonin Uptake Inhibitors
Nicotinic Receptors
Cholinergic Receptors
Binding Sites
Dizocilpine Maleate
Paroxetine
Valine
Torpedo
Phencyclidine
Leucine
Molecular mechanics
Coulomb interactions
Mechanics
Static Electricity
Ion Channels
Antidepressive Agents
Mouth
Ions
Fluxes

Keywords

  • Ca influx
  • Conformational states
  • Molecular modeling
  • Nicotinic acetylcholine receptors
  • Radioligand binding
  • Serotonin selective reuptake inhibitors

Cite this

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abstract = "Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit hα1β1γδ AChR-induced Ca2+ influx with higher potencies than dizocilpine. The potency of fluoxetine is increased ∼10-fold after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-3H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits [3H]dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13′) and leucine (position 9′) rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20′, 21′, and 24′. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20′) rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization.",
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Inhibitory mechanisms and binding site location for serotonin selective reuptake inhibitors on nicotinic acetylcholine receptors. / Arias, Hugo R.; Feuerbach, Dominik; Bhumireddy, Pankaj; Ortells, Marcelo O.

In: International Journal of Biochemistry and Cell Biology, Vol. 42, No. 5, 01.05.2010, p. 712-724.

Research output: Contribution to journalArticle

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T1 - Inhibitory mechanisms and binding site location for serotonin selective reuptake inhibitors on nicotinic acetylcholine receptors

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AB - Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit hα1β1γδ AChR-induced Ca2+ influx with higher potencies than dizocilpine. The potency of fluoxetine is increased ∼10-fold after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-3H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits [3H]dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13′) and leucine (position 9′) rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20′, 21′, and 24′. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20′) rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization.

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