Duarte, YorleyRojas, MaximilianoCanan, JonathanPérez, Edwin G.González-Nilo, FernandoGarcía-Colunga, Jesús2023-03-312023-03-312021-02Molecules Volume 26, Issue 42 February 2021 Article number 9981420-3049https://repositorio.unab.cl/xmlui/handle/ria/48091Indexación: ScopusSeveral antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a noncompetitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological pro le modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited IChwith the order: Norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.enAllosteric modulatorsAntidepressantsBiological activityHippocampusIn silico studiesα7 nicotinic acetylcholine receptorsArtículoAtribución 4.0 Internacional (CC BY 4.0)10.3390/molecules26040998