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Research ArticleDrug Discovery and Translational Medicine

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

Hugo R. Arias, Nikolai B. Fedorov, Lisa C. Benson, Patrick M. Lippiello, Greg J. Gatto, Dominik Feuerbach and Marcelo O. Ortells
Journal of Pharmacology and Experimental Therapeutics January 2013, 344 (1) 113-123; DOI: https://doi.org/10.1124/jpet.112.197905
Hugo R. Arias
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Nikolai B. Fedorov
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Lisa C. Benson
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Patrick M. Lippiello
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Greg J. Gatto
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Dominik Feuerbach
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Marcelo O. Ortells
Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, California (H.R.A); Preclinical Research, Targacept, Inc., Winston Salem, North Carolina (N.B.F., L.C.B., P.M.L., G.J.G.); Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland (D.F., M.O.O.); and Faculty of Medicine (D.F.) and CONICET (M.O.O.), University of Morón, Argentina
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Abstract

The interaction of the selective norepinephrine reuptake inhibitor (−)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca2+-influx results indicate that (−)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (−)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (−)-reboxetine binds to the luminal [3H]imipramine site. The results indicate that, although (−)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (−)-reboxetine progressively inhibits the hα4β2 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 (−)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6′ and 14′. In addition, we found a (−)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (−)-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 (−)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs.

Footnotes

  • This research was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (to M.O.).

  • dx.doi.org/10.1124/jpet.112.197905.

  • Received June 28, 2012.
  • Accepted September 25, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 1
1 Jan 2013
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Research ArticleDrug Discovery and Translational Medicine

Reboxetine and hα4β2 nAChRs

Hugo R. Arias, Nikolai B. Fedorov, Lisa C. Benson, Patrick M. Lippiello, Greg J. Gatto, Dominik Feuerbach and Marcelo O. Ortells
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 113-123; DOI: https://doi.org/10.1124/jpet.112.197905

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Research ArticleDrug Discovery and Translational Medicine

Reboxetine and hα4β2 nAChRs

Hugo R. Arias, Nikolai B. Fedorov, Lisa C. Benson, Patrick M. Lippiello, Greg J. Gatto, Dominik Feuerbach and Marcelo O. Ortells
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 113-123; DOI: https://doi.org/10.1124/jpet.112.197905
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