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

摘要

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 a3b4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction. (C) 2014 Elsevier Ltd. All rights reserved.