Different interaction between tricyclic antidepressants and mecamylamine with the human alpha3beta4 nicotinic acetylcholine receptor ion channel.
The interaction of tricyclic antidepressants (TCAs) with the human (h)alpha3beta4 nicotinic acetylcholine receptor (AChR) in different conformational states was compared with that for mecamylamine by using functional and structural approaches including, Ca(2+) influx, radioligand binding, and molecular docking. The results established that: (a) [(3)H]imipramine binds to a single site with relatively high affinity (K(d) = 0.41 +/- 0.04 microM), (b) imipramine inhibits [(3)H]imipramine binding to the resting/kappa-bungarotoxin-bound AChR (K(i) = 0.68 +/- 0.08 microM) with practically the same affinity as to the desensitized/epibatidine-bound AChR (K(i) = 0.83 +/- 0.08 microM), suggesting that TCAs do not discriminate between these conformational states, and (c) although TCAs (IC(50) approximately 1.8-2.7 microM) and mecamylamine (IC(50) = 3.3 +/- 0.4 microM) inhibit (+/-)-epibatidine-induced Ca(2+) influx with potencies in the same concentration range, TCAs (K(i) approximately 1-3.6 microM), but not mecamylamine (apparent IC(50) approximately 0.2 mM), inhibit [(3)H]imipramine binding to halpha3beta4 AChRs in different conformational states. This is explained by our docking results where imipramine, in the neutral and protonated states, interacts with the leucine (position 9') and valine/phenylalanine (position 13') rings, whereas protonated mecamylamine (>99% at physiological pH) interacts with the outer ring (position 20'). Our data indicate that TCAs bind to overlapping sites located between the serine and valine/phenylalanine rings in the halpha3beta4 AChR ion channel, whereas protonated mecamylamine can be attracted to the channel mouth before blocking ion flux by interacting with a luminal site in its neutral state.
Arias
Hugo R
HR
Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ 85308, USA. harias@midwestern.edu
Targowska-Duda
Katarzyna M
KM
Feuerbach
Dominik
D
Sullivan
Carl J
CJ
Maciejewski
Ryszard
R
Jozwiak
Krzysztof
K
D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007099:Imipramine / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects; D008464:Mecamylamine / Q000494:pharmacology*; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*
D000929:Antidepressive Agents, Tricyclic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007473:Ion Channels; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D008464:Mecamylamine; C082748:epibatidine; D007099:Imipramine; D002118:Calcium