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; Lopez, John; Morelo, Guibeth; Tapia, Ricardo A.; Arias, Hugo R.

doi:10.1039/c3md00042g

Cited by 9 publications

(12 citation statements)

References 26 publications

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“…Our finding that the improvement of cognitive function is attributed to an nAChR antagonist instead of agonist responses is consistent with other studies demonstrating (i) significant attenuation of memory impairment in mice using low doses of the nicotinic antagonist, mecamylamine ; (ii) the effect of a nicotinic antagonist on memory improvement in adults with ADHD ; and (iii) enhanced attention elicited using the α 4 β 2‐nAChR antagonist DH β E and α 7 nAChR antagonist MLA . More recently, the interest in nAChR antagonists has increased due to the diversity of therapeutic applications .…”

Section: Resultssupporting

confidence: 91%

Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment

et al. 2015

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Structure modification of a lead compound (NSC13378) was accomplished in the present work by an in silico target-based design aimed at ligands acting on the nicotinic acetylcholine receptor (nAChR) for neurodegenerative diseases. A 187-compound focused library derived from the scaffold of the lead compound was screened against acetylcholine-binding proteins (AChBPs). Six compounds were identified and synthesized for binding and biological evaluations. Five compounds were found to bind with AChBPs. Among these compounds, QN1 and BZ1 showed the highest affinity binding with AChBP, with Kd values of 260 and 10 nm, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are a4b2-nAChR antagonists. QN1 and BZ1 significantly alleviated the memory impairment caused by the muscarinic cholinergic antagonist scopolamine (p < 0.05) in mice. Our findings demonstrate the potential of nAChR antagonists in drug development for cognitive impairments.

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Section: Resultssupporting

confidence: 91%

Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment

et al. 2015

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“…For the chemical synthesis of new piperidine derivatives, commercial reagents, and solvents were used (Sigma-Aldrich and MERCK), employing previously described synthetic methodologies ( Roy et al, 1999 ; Peters et al, 2006 ; Pérez et al, 2012 , 2013 ; Arias et al, 2013 ; Dang et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, our group developed the selective antagonists for α7 nAChRs compounds 1 and 2 ( Arias et al, 2013 ; Pérez et al, 2013 ; López et al, 2015 ; Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…There are two important criteria for generating α7 nAChR antagonists: (a) a center containing a nitrogen atom with a positive charge (cationic center), which can interact with the “aromatic box” of the nAChR. In this regard, the pyridinic nitrogen atom of nicotine ( Figure 2 , compound 3 ), alkylated with long aliphatic chains (3–9 atoms of carbon), results in a potent and selective antagonist for nAChRs ( Figure 2 , compounds 4 and 5 ) ( Crooks et al, 1995 ; Wilkins et al, 2002 ); (b) and alkyl groups located at the “ para ” position of an aromatic ring, which are important for van der Waals interactions with the amino acid residues of the complementary (-)-side, relevant for the selectivity toward the α7 subtype ( Crooks et al, 1995 ; Arias et al, 2013 ; Pérez et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors

et al. 2018

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The α7 nicotinic acetylcholine receptor (nAChR) is expressed in neuronal and non-neuronal cells and is involved in several physiopathological processes, and is thus an important drug target. We have designed and synthesized novel piperidine derivatives as α7 nAChR antagonists. Thus, we describe here a new series of 1-[2-(4-alkoxy-phenoxy-ethyl)]piperidines and 1-[2-(4-alkyloxy-phenoxy-ethyl)]-1-methylpiperidinium iodides (compounds 11a-11c and 12a-12c), and their actions on α7 nAChRs. The pharmacological activity of these compounds was studied in rat CA1 hippocampal interneurons by using the whole-cell voltage-clamp technique. Inhibition of the choline-induced current was less for 11a-11c than for the methylpiperidinium iodides 12a-12c and depended on the length of the aliphatic chain. Those compounds showing strong effects were studied further using molecular docking and molecular dynamics simulations. The strongest and non-voltage dependent antagonism was shown by 12a, which could establish cation–π interactions with the principal (+)-side and van der Waals interactions with the complementary (-)-side in the α7 nAChRs. Furthermore, compound 11a forms hydrogen bonds with residue Q115 of the complementary (-)-side through water molecules without forming cation–π interactions. Our findings have led to the establishment of a new family of antagonists that interact with the agonist binding cavity of the α7 nAChR, which represent a promising new class of compounds for the treatment of pathologies where these receptors need to be negatively modulated, including neuropsychiatric disorders as well as different types of cancer.

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“…[28][29][30] Indole might be used as a promising scaffold in the development of novel nicotinic antagonists. 31 The present study is used to predict the optimized molecular structure and vibrational studies of the NICA molecule with the aid of quantum chemical calculations. 32 The vibrational investigations were carried out based on the potential energy distribution (PED) calculation.…”

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confidence: 99%

Spectroscopic characterization, DFT studies, molecular docking and cytotoxic evaluation of 4‐nitro‐indole‐3‐carboxaldehyde: A potent lung cancer agent

Jeyaseelan¹,

Benial²

2020

J of Molecular Recognition

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The 4-nitro-1H-indole-carboxaldehyde (NICA) molecule was characterized experimentally using FT-IR, FT-Raman and UV-Vis spectra, and it was studied theoretically using DFT calculations. The optimized structure of the NICA molecule was determined by DFT calculations using B3LYP functional with cc-pVTZ basis set. The electron localization function (ELF) and local orbital localizer (LOL) studies were performed to visualize the electron delocalization in the molecule. The experimental and theoretical wavenumbers of the title molecule were assigned using VEDA 4.0 program. The charge delocalization and stability of the title molecule were investigated using natural bond orbital (NBO) analysis. Frontier molecular orbitals (FMOs) and related molecular properties were calculated. UV-Vis spectrum was calculated theoretically and validated experimentally. The reactive sites of the molecule were studied from the MEP surface and Fukui function analysis. The molecular docking analysis reveals that the NICA ligand shows better inhibitory activity against RAS, which causes lung cancer. The in vitro cytotoxic activity of the molecule against human lung cancer cell lines (A549) was determined by MTT assay. Thus, the NICA molecule can be used as a potential candidate for the development of the drug against lung cancer.

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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

Cited by 9 publications

References 26 publications

Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment

Design and Synthesis of Nicotinic Acetylcholine Receptor Antagonists and their Effect on Cognitive Impairment

Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors

Spectroscopic characterization, DFT studies, molecular docking and cytotoxic evaluation of 4‐nitro‐indole‐3‐carboxaldehyde: A potent lung cancer agent

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