Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor

[Display omitted] 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 micr...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2014-12, Vol.22 (24), p.6846-6856
Main Authors: Jozwiak, Krzysztof, Targowska-Duda, Katarzyna M., Kaczor, Agnieszka A., Kozak, Joanna, Ligeza, Agnieszka, Szacon, Elzbieta, Wrobel, Tomasz M., Budzynska, Barbara, Biala, Grazyna, Fornal, Emilia, Poso, Antti, Wainer, Irving W., Matosiuk, Dariusz
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Cell Line
Dextromethorphan
Dextromethorphan - chemical synthesis
Dextromethorphan - chemistry
Dextromethorphan - pharmacology
Ligands
Lipid Bilayers - chemistry
Lipid Bilayers - metabolism
Male
Molecular Docking Simulation
Motor Activity - drug effects
Nicotinic acetylcholine receptors
Nicotinic Antagonists - chemical synthesis
Nicotinic Antagonists - chemistry
Nicotinic Antagonists - pharmacology
Non-competitive inhibitors
Patch-Clamp Techniques
Phosphatidylcholines - chemistry
Protein Binding
Protein Structure, Tertiary
Rats
Rats, Wistar
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - metabolism
α3β4 nicotinic acetylcholine receptor
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.10.036