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Interaction of fluoxetine and paroxetine with muscle nicotinic acetylcholine receptors
Author(s) -
Andersen John David,
Feuerbach Dominik,
Ortells Marcelo O,
Arias Hugo
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.986.16
Subject(s) - dizocilpine , chemistry , fluoxetine , acetylcholine receptor , nicotinic agonist , pharmacology , nicotinic acetylcholine receptor , protonation , stereochemistry , receptor , biophysics , serotonin , biochemistry , antagonist , biology , ion , organic chemistry
The interaction of serotonin selective reuptake inhibitors (SSRIs) (i.e., fluoxetine and paroxetine) with muscle nicotinic acetylcholine receptors (AChRs) in different conformational states was compared to that for dizocilpine by using functional and structural methods. The results established that: (a) SSRIs inhibit (±)‐epibatidine‐induced Ca 2+ influx with higher potencies than dizocilpine, (b) SSRIs inhibit [ 3 H]TCP binding to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits [ 3 H]dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where fluoxetine and dizocilpine in the neutral state interact with the valine (position 13′) and leucine (position 9′) rings. Protonated fluoxetine has two potential binding sites, one located at or near the outer ring (position 20′), and another that overlaps the domain for the neutral molecules and for protonated dizocilpine. The high proportion of protonated fluoxetine and dizocilpine at pH 7.4 (>95%) suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel, in a site shared with PCP. Support: Science Foundation Arizona.