title: Structural and functional interaction of (±)-2-(N-tert-butylamino)-3'-iodo-4'-azidopropiophenone, a photoreactive bupropion derivative, with nicotinic acetylcholine receptors.
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.
authors.affiliation: Department of Medical Education, College of Medicine, California Northstate University, Elk Grove, CA 95757, USA.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.forename: Shaili
authors.initials: S
authors.lastname: Aggarwal
authors.forename: David J
authors.initials: DJ
authors.lastname: Lapinsky
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001386:Azides / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016642:Bupropion / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D010777:Photochemistry; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D012208:Rhabdomyosarcoma / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D061485:Tobacco Use Cessation Devices
chemical_list: C572068:2-(N-tert-butylamino)-3'-iodo-4'-azidopropiophenone; D018687:Antidepressive Agents, Second-Generation; D001386:Azides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D011978:Receptors, Nicotinic; D016642:Bupropion; C082748:epibatidine