Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human α4β2 and α7 nicotinic acetylcholine receptors

Edwin G. Pérez, Cristian Ocampo, Dominik Feuerbach, Jhon J. López, Guibeth L. Morelo, Ricardo A. Tapia, Hugo R. Arias

Research output: Contribution to journalArticle

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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) α7 and α4β2 nicotinic acetylcholine receptors (nAChRs). The inhibitory activity of the compounds was determined by Ca2+ influx assays on cells expressing either the hα7 or hα4β2 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 [3H] methyllycaconitine, [3H]cytisine, and [3H]imipramine. The results established that the compounds inhibit the nAChRs by a competitive mechanism and that the potencies are higher for the hα7 nAChR compared to that for the hα4β2 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 hα7 nAChR subtype. Molecular docking results indicate that the hydroxyl group forms a hydrogen bond with the carbonyl group at α7-Gln116, but not at β2-Phe115, supporting the observed receptor selectivity at the molecular level.

Original languageEnglish
Pages (from-to)1166-1170
Number of pages5
JournalMedChemComm
Volume4
Issue number8
DOIs
StatePublished - 1 Aug 2013
Externally publishedYes

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Nicotinic Receptors
Iodides
Hydroxyl Radical
Assays
Derivatives
Radioligand Assay
Imipramine
Benzene
Functional groups
Hydrogen
Hydrogen bonds
Substitution reactions
Cells
Pharmacology
cytisine
methyllycaconitine

Cite this

Pérez, Edwin G. ; Ocampo, Cristian ; Feuerbach, Dominik ; López, Jhon J. ; Morelo, Guibeth L. ; Tapia, Ricardo A. ; Arias, Hugo R. / Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human α4β2 and α7 nicotinic acetylcholine receptors. In: MedChemComm. 2013 ; Vol. 4, No. 8. pp. 1166-1170.
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Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human α4β2 and α7 nicotinic acetylcholine receptors. / Pérez, Edwin G.; Ocampo, Cristian; Feuerbach, Dominik; López, Jhon J.; Morelo, Guibeth L.; Tapia, Ricardo A.; Arias, Hugo R.

In: MedChemComm, Vol. 4, No. 8, 01.08.2013, p. 1166-1170.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel 1-(1-benzyl-1H-indol-3-yl)-N,N,N-trimethylmethanaminium iodides are competitive antagonists for the human α4β2 and α7 nicotinic acetylcholine receptors

AU - Pérez, Edwin G.

AU - Ocampo, Cristian

AU - Feuerbach, Dominik

AU - López, Jhon J.

AU - Morelo, Guibeth L.

AU - Tapia, Ricardo A.

AU - Arias, Hugo R.

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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) α7 and α4β2 nicotinic acetylcholine receptors (nAChRs). The inhibitory activity of the compounds was determined by Ca2+ influx assays on cells expressing either the hα7 or hα4β2 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 [3H] methyllycaconitine, [3H]cytisine, and [3H]imipramine. The results established that the compounds inhibit the nAChRs by a competitive mechanism and that the potencies are higher for the hα7 nAChR compared to that for the hα4β2 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 hα7 nAChR subtype. Molecular docking results indicate that the hydroxyl group forms a hydrogen bond with the carbonyl group at α7-Gln116, but not at β2-Phe115, supporting the observed receptor selectivity at the molecular level.

AB - 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) α7 and α4β2 nicotinic acetylcholine receptors (nAChRs). The inhibitory activity of the compounds was determined by Ca2+ influx assays on cells expressing either the hα7 or hα4β2 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 [3H] methyllycaconitine, [3H]cytisine, and [3H]imipramine. The results established that the compounds inhibit the nAChRs by a competitive mechanism and that the potencies are higher for the hα7 nAChR compared to that for the hα4β2 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 hα7 nAChR subtype. Molecular docking results indicate that the hydroxyl group forms a hydrogen bond with the carbonyl group at α7-Gln116, but not at β2-Phe115, supporting the observed receptor selectivity at the molecular level.

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