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
Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, 4a Chodzki St., PL-20093 Lublin, Poland.
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.
Bioorg Med Chem. 2014 Dec 15;22(24):6846-56. doi: 10.1016/j.bmc.2014.10.036. Epub 2014 Oct 31.
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.
合成了右美沙芬的9种N-烷基化衍生物，并将其作为α3β4烟碱型乙酰胆碱受体（nAChRs）的非竞争性抑制剂进行研究。使用膜片钳技术测定其对α3β4烟碱型乙酰胆碱受体的体外活性，活性范围在微摩尔级别。利用同源建模、分子对接以及在POPC膜中配体-受体复合物的分子动力学来寻找N-烷基化右美沙芬衍生物与α3β4 nAChR的相互作用模式。这些化合物与右美沙芬类似，与α3β4 nAChR离子通道的中部相互作用。最后，行为测试证实了所研究化合物在治疗成瘾方面的潜在应用。
