Different interaction between tricyclic antidepressants and mecamylamine with the human α3β4 nicotinic acetylcholine receptor ion channel

Arias, Hugo R.; Targowska-Duda, Katarzyna M.; Feuerbach, Dominik; Sullivan, Carl J.; Maciejewski, Ryszard; Jóźwiak, Krzysztof

doi:10.1016/j.neuint.2010.01.011

Cited by 32 publications

(71 citation statements)

References 34 publications

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“…Inhibitory mechanisms have also been reported for tricyclic antidepressants, bupropion, and selective serotonin reuptake inhibitors in muscle- (Arias et al, 2009;Arias et al, 2010a;Gumilar et al, 2003;Lopez-Valdes and Garcia-Colunga, 2001) and neuronal-type nAChRs (Arias et al, 2010b;Arias et al, 2010c;Arias et al, 2010d;Gumilar and Bouzat, 2008;LopezValdes and Garcia-Colunga, 2001). This evidence suggests that there is a basic mechanistic motif for structurally different antidepressants mediating the inhibition of distinct nAChRs.…”

Section: Discussionmentioning

confidence: 90%

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

Arias

Fedorov²,

Benson³

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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The interaction of the selective norepinephrine reuptake inhibitor (2)-reboxetine with the human a4b2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca 21-influx results indicate that (2)-reboxetine does not activate ha4b2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced ha4b2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiologybased functional approach suggest that (2)-reboxetine may act via open channel block; therefore, it is capable of producing a usedependent type of inhibition of the ha4b2 nAChR function. We tested whether (2)-reboxetine binds to the luminal [ 3 H]imipramine site. The results indicate that, although (2)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized ha4b2 nAChR ion channels. Patch-clamp results also indicate that (2)-reboxetine progressively inhibits the ha4b2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (2)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 69 and 149. In addition, we found a (2)-reboxetine conformer that docks in the helix bundle of the a4 subunit, near the middle region. According to molecular dynamics simulations, (2)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (2)-reboxetine may be produced (at least partially) by its inhibitory action on ha4b2 nAChRs.

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Section: Discussionmentioning

confidence: 90%

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

Arias

Fedorov²,

Benson³

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

Self Cite

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show abstract

“…In this regard, the first step involves the construction of the nAChR target by molecular homology [21,22,28,[31][32][33], using the Torpedo nAChR model (Fig. 1) as a structural template.…”

Section: In Silico Methodsmentioning

confidence: 99%

“…1) as a structural template. The antidepressants under study were built in the protonated and neutral state, and subsequently docked in the nAChR model [21,22,28,[31][32][33]. Finally, to verify whether the ligand orientation is stable within each binding site, molecular dynamics simulations were performed [28,[31][32][33].…”

Section: In Silico Methodsmentioning

confidence: 99%

“…Table 2 shows the inhibitory potency (IC 50 ) of structurally and functionally different antidepressants studied in several laboratories. Among them we can name tricyclic antidepressants (TCAs), including imipramine, amitriptyline, doxepin, nortriptyline, and desipramine [19][20][21][22]; norepinephrine selective reuptake inhibitors (NSRIs), including (-)-reboxetine [20] and nisoxetine (not in clinical use); and DA/NE reuptake inhibitors such as (±)-bupropion [23,24]. Fig.…”

Section: Link Between Neuronal Nachrs and Depressionmentioning

confidence: 99%

“…TCAs act primarily by blocking the 5-HT and/or NE transporters, resulting in elevation of the synaptic concentration of these neurotransmitters, and therefore an enhancement of the serotonergic and adrenergic neuronal pathways. There is also evidence indicating that TCAs inhibit both muscle [54] and neuronal [19,21,22] nAChRs by noncompetitive mechanisms ( Table 2). Other members of the Cys-loop LGIC superfamily are inhibited by TCAs as well [55].…”

Section: Non-overlapping Interactions Between Tricyclic Antidepressanmentioning

confidence: 99%

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Phytochemical of Indonesian Macaranga and their Cytotoxic Properties Against P388 Cells

Syah

Mujahidin²,

Juliawaty³

et al. 2013

TOPROCJ

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Over the last decades, several computational (in silico) methods have been developed and applied to test pharmacological hypotheses. An important hypothesis is that the therapeutic activity of many commonly used antidepressants may be partially mediated through the inhibition of different nicotinic acetylcholine receptors (nAChRs). This is based on pathologic conditions where the activity of the cholinergic system is exacerbated compared to the adrenergic system. Different in silico methods, including comparative/homology modeling, molecular docking, and molecular dynamics simulations, have been employed to study the interactions between several classes of antidepressants with distinct nAChR subtypes. More specifically, these methods were used to structurally characterize the antidepressant binding sites and to better understand their inhibitory mechanisms. This review focuses on computational methods that were found important in explaining and supporting several experimental results concerning the interaction of antidepressants with different nAChR subtypes. Among the studied antidepressants are norepinephrine selective reuptake inhibitors [e.g., (-)-reboxetine] as well as less selective antidepressants such as dopamine/norepinephrine reuptake inhibitors [e.g., (±)-bupropion and its derivatives], tricyclic antidepressants (e.g., imipramine), and (±)-mecamylamine and its enantiomers.

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Discriminative Stimulus Properties of S(−)-Nicotine: “A Drug for All Seasons”

Rosecrans

Young

2017

Current Topics in Behavioral Neurosciences

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S(-)-Nicotine is the major pharmacologically active substance in tobacco and can function as an effective discriminative stimulus in both experimental animals and humans. In this model, subjects must detect and communicate the nicotine drug state versus the non-drug state. This review describes the usefulness of the procedure to study nicotine, presents a general overview of the model, and provides some relevant methodological details for the establishment of this drug as a stimulus. Once established, the (-)-nicotine stimulus can be characterized for dose response and time course effects. Moreover, tests can be conducted to determine the similarity of effects produced by test drugs to those produced by the training dose of nicotine. Such tests have shown that the stimulus effects of nicotine are stereoselective [S(-)-nicotine >R(+)-nicotine] and that other "natural" tobacco alkaloids and (-)-nicotine metabolites can produce (-)-nicotine-like effects, but these drugs are much less potent than (-)-nicotine. Stimulus antagonism tests with mecamylamine and DHβE (dihydro-β-erythroidine) indicate that the (-)-nicotine stimulus is mediated via α4β2 nicotinic acetylcholine receptors (nAChRs) in brain; dopamine systems also are likely involved. Individuals who try to cease their use of nicotine-based products are often unsuccessful. Bupropion (Zyban) and varenicline (Chantix) may be somewhat effective as anti-smoking medications because they probably produce stimulus effects that serve as suitable substitutes for (-)-nicotine in the individual who is motivated to quit smoking. Finally, it is proposed that future drug discrimination studies should apply the model to the issue of maintenance of abstinence from (-)-nicotine-based products.

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Different interaction between tricyclic antidepressants and mecamylamine with the human α3β4 nicotinic acetylcholine receptor ion channel

Cited by 32 publications

References 34 publications

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

Phytochemical of Indonesian Macaranga and their Cytotoxic Properties Against P388 Cells

Discriminative Stimulus Properties of S(−)-Nicotine: “A Drug for All Seasons”

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