Interaction of fluoxetine and paroxetine with muscle nicotinic acetylcholine receptors.

ANDERSEN, J.D.; FEUERBACH, D; ORTELLS, MARCELO OSCAR; ARIAS, H.

Glendale

Jornada; 8th Annual Dr. Kenneth A. Suarez Student Research Day; 2010

Midwestern University

Functional and structural approaches were used to examine the inhibitory mechanisms and binding sitelocation for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholinereceptors (AChRs) in different conformational states. The results establish that: (a) fluoxetineand paroxetine inhibit h11 AChR-induced Ca2+ influx with higher potencies than dizocilpine. Thepotency of fluoxetine is increased ¡­10-fold after longer pre-incubation periods, which is in agreementwith the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs elicited by theseantidepressants, (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 higheraffinities compared to the resting AChR, and (c) fluoxetine inhibits [3H]dizocilpine binding to the desensitizedAChR, suggesting a mutually exclusive interaction. This is supported by our molecular dockingresults where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with thehighest 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 fluoxetineat positions 20, 21, and 24. Protonated dizocilpine bridges these two binding domains by interactingwith the valine and outer (position 20) rings. The high proportion of protonated fluoxetine and dizocilpinecalculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouthbefore binding deeper within the AChR ion channel between the leucine and valine rings, a domain sharedwith phencyclidine, finally blocking ion flux and inducing AChR desensitization.