Perez, EG, Ocampo, C, Feuerbach, D, Lopez, JJ, Morelo, GL, Tapia, RA and Arias, HR (2013) Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human alpha4beta2 and alpha7 nicotinic acetylcholine receptors. MedChemComm. pp. 1166-1170.

Abstract

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) alpha7 and alpha4beta2 nicotinic acetylcholine receptors (nAChRs). The inhibitory activity of the compounds was determined by Ca<sup>2+</sup> influx assays on cells expressing either the halpha7 or halpha4beta2 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 [<sup>3</sup>H] methyllycaconitine, [<sup>3</sup>H]cytisine, and [<sup>3</sup>H]imipramine. The results established that the compounds inhibit the nAChRs by a competitive mechanism and that the potencies are higher for the halpha7 nAChR compared to that for the halpha4beta2 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 halpha7 nAChR subtype. Molecular docking results indicate that the hydroxyl group forms a hydrogen bond with the carbonyl group at alpha7-Gln116, but not at beta2-Phe115, supporting the observed receptor selectivity at the molecular level. 2013 The Royal Society of Chemistry

Item Type:	Article
Additional Information:	pubid: 162 nvp_institute: NIBR contributor_address: (Perez, Ocampo, Lopez, Tapia) Facultad de Quimica, Pontificia Universidad Catolica de Chile, Av. Vicuna Mackenna 4860, Santiago 6094411, Chile (Feuerbach) Novartis Institutes for Biomedical Research, Basel, Switzerland (Morelo) Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile (Arias) Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA 95757, United States
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/21992