Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human alpha 4 beta 2 and alpha 7 nicotinic acetylcholine receptors

作者：Perez Edwin G^*; Ocampo Cristian; Feuerbach Dominik; Lopez Jhon J; Morelo Guibeth L; Tapia Ricardo A; Arias Hugo R

来源：Medchemcomm, 2013, 4(8): 1166-1170.

DOI：10.1039/c3md00042g

This work presents the synthesis and the pharmacological characterization of a series of novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodide derivatives at the human (h) alpha 7 and alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs). The inhibitory activity of the compounds was determined by Ca2+ influx assays on cells expressing either the h alpha 7 or h alpha 4 beta 2 nAChR subtype. To determine whether the observed inhibitory activity is mediated by a competitive or non-competitive mechanism, additional radioligand binding assays were performed using [H-3]methyllycaconitine, [H-3]cytisine, and [H-3]imipramine. The results established that the compounds inhibit the nAChRs by a competitive mechanism and that the potencies are higher for the h alpha 7 nAChR compared to that for the h alpha 4 beta 2 nAChR. Substitutions with oxygenated functional groups on the benzene ring increase the receptor selectivity. In particular, the hydroxyl derivatives 4b and 4c present the highest selectivity for the h alpha 7 nAChR subtype. Molecular docking results indicate that the hydroxyl group forms a hydrogen bond with the carbonyl group at alpha 7-Gln116, but not at beta 2-Phe115, supporting the observed receptor selectivity at the molecular level.

• 出版日期2013-8