Inhibitory mechanisms and binding site location for serotonin selective reuptake inhibitors on nicotinic acetylcholine receptors.
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 h alpha1beta1 gammadelta AChR-induced Ca(2+) influx with higher potencies than dizocilpine. The potency of fluoxetine is increased approximately 10-fold after longer pre-incubation periods, which is in agreement with the enhancement of [(3)H]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-(3)H(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 [(3)H]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.
Arias
Hugo R
HR
Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, 19555 N. 59th Ave Glendale, AZ, USA. harias@midwestern.edu
Feuerbach
Dominik
D
Bhumireddy
Pankaj
P
Ortells
Marcelo O
MO
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D004557:Electric Organ / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D017374:Paroxetine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D014101:Torpedo
D016291:Dizocilpine Maleate; D005473:Fluoxetine; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D017374:Paroxetine; D020033:Protein Isoforms; D011978:Receptors, Nicotinic; D017367:Selective Serotonin Reuptake Inhibitors