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Interaction of tricyclic antidepressants with the ha3β4 nicotinic receptor
Author(s) -
Ahmad Ali H,
Feuerbach Dominick,
Jozwiak Krzysztof,
Arias Hugo R
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.620.4
Subject(s) - mecamylamine , imipramine , chemistry , tricyclic , nicotinic agonist , stereochemistry , protonation , nicotinic acetylcholine receptor , binding site , acetylcholine receptor , biophysics , receptor , biochemistry , ion , biology , medicine , organic chemistry , alternative medicine , pathology
The interaction of tricyclic antidepressants (TCAs) with human (h)a3β4 nicotinic acetylcholine receptor (AChR) was compared to that for mecamylamine. The results established that: (a) [3H]imipramine binds to a single site with high affinity (Kd = 0.41 ± 0.04 μM), (b) imipramine inhibits [3H]imipramine binding to resting AChR with the same affinity as to desensitized AChR, suggesting that TCAs do not distinguish between these conformational states, (c) imipramine inhibits [3H]ibogaine binding, suggesting mutual interaction between both compounds, (d) both TCAs and mecamylamine inhibit (±)‐epibatidine‐induced Ca2+ influx with potencies in the same concentration range, but only TCAs inhibit [3H]imipramine binding to ha3β4 AChRs. This is supported by our molecular docking results, where imipramine, in the neutral and protonated states, interacts with the leucine (position 9′) and valine/phenylalanine (position 13′) rings, while protonated mecamylamine interacts with the outer ring (position 20′). Our data suggest that TCAs and ibogaine bind to overlapping sites located between the serine and valine/phenylalanine rings in the ha3β4 AChR ion channel, while protonated mecamylamine can be attracted to the channel mouth before blocking ion flux by interacting with a luminal site in its neutral state. Support: Science Foundation Arizona.