title: Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor.
abstract: 9 N-alkylated derivatives of dextromethorphan are synthesized and studied as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptors (nAChRs). In vitro activity towards α3β4 nicotinic acetylcholine receptor is determined using a patch-clamp technique and is in the micromolar range. Homology modeling, molecular docking and molecular dynamics of ligand-receptor complexes in POPC membrane are used to find the mode of interactions of N-alkylated dextromethorphan derivatives with α3β4 nAChR. The compounds, similarly as dextromethorphan, interact with the middle portion of α3β4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction.
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Targowska-Duda
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland; School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland; Department of Anatomy, Medical University of Lublin, 4 Jaczewskiego St., PL-20090 Lublin, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kozak
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ligeza
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Szacon
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Wrobel
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Budzynska
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Biala
authors.affiliation: Department of Chemistry, Catholic University of Lublin, al. Krasnicka 102, PL-20718 Lublin, Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Fornal
authors.affiliation: School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, PO Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Laboratory of Clinical Investigation, Division of Intramural Research Programs, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, 4a Chodzki St., PL-20093 Lublin, Poland. Electronic address: darek.matosiuk@umlub.pl.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Matosiuk
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003915:Dextromethorphan / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D009043:Motor Activity / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010713:Phosphatidylcholines / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D008051:Lipid Bilayers; D018733:Nicotinic Antagonists; D010713:Phosphatidylcholines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D003915:Dextromethorphan; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Dextromethorphan; Nicotinic acetylcholine receptors; Non-competitive inhibitors; α3β4 nicotinic acetylcholine receptor