Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of alpha sub(3) beta sub(4) nicotinic acetylcholine receptor

9 N-alkylated derivatives of dextromethorphan are synthesized and studied as non-competitive inhibitors of alpha 3 beta 4 nicotinic acetylcholine receptors (nAChRs). In vitro activity towards alpha 3 beta 4 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 alpha 3 beta 4 nAChR. The compounds, similarly as dextromethorphan, interact with the middle portion of alpha 3 beta 4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction.