Structural and functional interaction of (±)-2-(N-tert-butylamino)-3′-iodo-4′-azidopropiophenone,a photoreactive bupropion derivative,with nicotinic acetylcholine receptors |
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| Institution: | 1. Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, CA 95757, USA;2. Novartis Institutes for Biomedical Research, Basel, Switzerland;3. Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland;4. Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA;2. Institute of Geosciences, Friedrich-Schiller University, Burgweg 11, D-07749 Jena, Germany;3. Karlsruhe Institute of Technology, ANKA Synchrotron Radiation Facility, Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany;4. Mössbauer Spectroscopy Division, Institute of Physics, Pedagogical University, ul. Podchor??ych 2, PL-30-084 Kraków, Poland;1. Programa de Pós-Graduação em Ciências Farmacêuticas e Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí - UNIVALI, CEP 88302-901, Itajaí, SC, Brazil;2. Centro Integrado de Pesquisas Oncohematológicas na Infância (CIPOI), Universidade Estadual de Campinas - UNICAMP, Campinas, SP, Brazil;1. Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction Group, Bordeaux, F-33000, France;2. Université de Bordeaux, Bordeaux, F-33000, France;3. Inserm U1208, Stem Cell and Brain Research Institute, 69500, Bron, France;4. Université Lyon 1, 69373, Lyon, France;5. Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, 95125, Italy;1. Department of Biochemistry & Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS 66506;2. Instituto de la Grasa (CSIC), Campus Universitario Pablo de Olavide, Ctra. de Utrera Km 1, 41013 Seville, Spain;3. School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong;4. Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong |
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| Abstract: | The pharmacological properties of (±)-2-(N-tert-butylamino)-3′-iodo-4′-azidopropiophenone (±)-SADU-3-72], a photoreactive analog of bupropion (BP), were characterized at different muscle nicotinic acetylcholine receptors (AChRs) by functional and structural approaches. Ca2+ influx results indicate that (±)-SADU-3-72 is 17- and 6-fold more potent than BP in inhibiting human (h) embryonic (hα1β1γδ) and adult (hα1β1εδ) muscle AChRs, respectively. (±)-SADU-3-72 binds with high affinity to the 3H]TCP site within the resting or desensitized Torpedo AChR ion channel, whereas BP has higher affinity for desensitized AChRs. Molecular docking results indicate that both SADU-3-72 enantiomers interact with the valine (position 13′) and serine (position 6′) rings. However, an additional domain, between the outer (position 20′) and valine rings, is observed in Torpedo AChR ion channels. Our results indicate that the azido group of (±)-SADU-3-72 may enhance its interaction with polar groups and the formation of hydrogen bonds at AChRs, thus supporting the observed higher potency and affinity of (±)-SADU-3-72 compared to BP. Collectively our results are consistent with a model where BP/SADU-3-72 and TCP bind to overlapping sites within the lumen of muscle AChR ion channels. Based on these results, we believe that (±)-SADU-3-72 is a promising photoprobe for mapping the BP binding site, especially within the resting AChR ion channel. |
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