Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors

Kaczor, Agnieszka A.; Karczmarzyk, Zbigniew; Fruziński, Andrzej; Pihlaja, Kalevi; Sinkkonen, Jari; Wiinamäki, Kirsti; Kronbach, Christiane; Unverferth, K.; Poso, Antti; Matosiuk, Dariusz

doi:10.1016/j.bmc.2013.12.013

Cited by 13 publications

(19 citation statements)

References 29 publications

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“…Each nAChRvarenicline model was inserted into 1-palmitoyl-2-oleoyl phosphatidylcholine membranes, solvated with water as described previously [40] and ions were added to neutralize the protein charges as described elsewhere [41]. Each nAChR model was first minimized and then subjected to 1-ns MD in NVT (constant number of particles, volume, and temperature) ensemble, followed by 15-ns MD in NPT (constant number of particles, pressure, and temperature) ensemble.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes

Arias

Feuerbach

Targowska-Duda

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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To determine the structural components underlying differences in affinity, potency, and selectivity of varenicline for several human (h) nicotinic acetylcholine receptors (nAChRs), functional and structural experiments were performed. The Ca2+ influx results established that: (a) varenicline activates (μM range) nAChR subtypes with the following rank sequence: hα7>hα4β4>hα4β2>hα3β4>>>hα1β1γδ; (b) varenicline binds to nAChR subtypes with the following affinity order (nM range): hα4β2~hα4β4>hα3β4>hα7>>>Torpedo α1β1γδ. The molecular docking results indicating that more hydrogen bond interactions are apparent for α4-containing nAChRs in comparison to other nAChRs may explain the observed higher affinity; and that (c) varenicline is a full agonist at hα7 (101%) and hα4β4 (93%), and a partial agonist at hα4β2 (20%) and hα3β4 (45%), relative to (±)-epibatidine. The allosteric sites found at the extracellular domain (EXD) of hα3β4 and hα4β2 nAChRs could explain the partial agonistic activity of varenicline on these nAChR subtypes. Molecular dynamics simulations show that the interaction of varenicline to each allosteric site decreases the capping of Loop C at the hα4β2 nAChR, suggesting that these allosteric interactions limit the initial step in the gating process. In conclusion, we propose that in addition to hα4β2 nAChRs, hα4β4 nAChRs can be considered as potential targets for the clinical activity of varenicline, and that the allosteric interactions at the hα3β4- and hα4β2-EXDs are alternative mechanisms underlying partial agonism at these nAChRs.

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Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes

Arias

Feuerbach

Targowska-Duda

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…In particular, a non-competitive mode of action can result in a better safety profile as reported for non-competitive antagonists of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors [19]. In the previous studies, we also constructed 3D models of GluK1 and GluK2 receptors and suggested that indolederived non-competitive antagonists can bind in the receptor transduction domain [11,14,15,20,21]. In this study, in order to investigate thermal behaviour of indole derivatives the TG-DSC and TG-FTIR methods were applied.…”

Section: Introductionmentioning

confidence: 83%

“…The investigated compounds were synthesized in the Fisher indolization reaction from the respective arylhydrazine hydrochloride and appropriate ketone in anhydrous boiling ethanol saturated with HCl followed by alkylation with alkyl halide (with application of sodium hydride). These compounds are a noncompetitive antagonists of kainate GluK1/GluK2 (GluKglutamatergic kainate receptors) receptors with low micromolar activity, and compound 2 is the most promising from the series [10,11]. Non-competitive antagonists of kainate receptors [10][11][12][13][14][15] can be considered promising compounds for the treatment of neurodegenerative diseases [16,17] as well as epilepsy [18].…”

Section: Introductionmentioning

confidence: 99%

“…These compounds are a noncompetitive antagonists of kainate GluK1/GluK2 (GluKglutamatergic kainate receptors) receptors with low micromolar activity, and compound 2 is the most promising from the series [10,11]. Non-competitive antagonists of kainate receptors [10][11][12][13][14][15] can be considered promising compounds for the treatment of neurodegenerative diseases [16,17] as well as epilepsy [18]. In particular, a non-competitive mode of action can result in a better safety profile as reported for non-competitive antagonists of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors [19].…”

Section: Introductionmentioning

confidence: 99%

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Thermal and spectroscopic studies of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles as non-competitive antagonists of GluK1/GluK2 receptors

Bartyzel

Kaczor

Głuchowska

et al. 2018

J Therm Anal Calorim

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This paper reports the thermal stability and thermal degradation of six derivatives of indole by means of TG-DSC (in air) and TG-FTIR (in nitrogen) techniques. The compounds were also characterized by infrared spectroscopy. In addition, IR spectra were calculated and compared with the experimental data. In particular, the potential energy distribution analysis was performed to assign IR signals. The studied compounds are characterized by good thermal stability in oxidizing and inert atmospheres which is important for potential medical application. Thermogravimetric measurements in air atmosphere showed that the decomposition of compounds proceeds in two or three main stages. The thermal degradation of compounds is preceded by the melting process. The pyrolysis of samples is a one-step process. Together with the analyses performed in nitrogen, the FTIR spectra of the evolved gas phase products were recorded. On the FTIR spectra of gaseous products, only the bands of water, carbon dioxide and carbon oxide molecules are present. In the case of indole derivatives containing the p-chlorobenzyl substituent in position 1, the bands of anisole, p-chlorotoluene and chlorobenzene also appear.

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“…1 (Kaczor et al ., 2012 ). We have also suggested a binding site for them in the receptor transduction domain (Kaczor et al ., 2014 ) which was enabled by the construction of whole receptor models (Kaczor et al ., 2008 , 2009 , 2014 ). Here we present further modifications, 2 – 7 , of the lead compound E099-25011, (1-ethyl-5-methoxy-2-(4-methoxyphenyl)-3-methylindole), 1 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and molecular docking of novel non-competitive antagonists of GluK2 receptor

Kaczor

Wróbel

Kronbach³

et al. 2014

Med Chem Res

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Here we present the synthesis, pharmacological activity, and molecular docking of novel non-competitive antagonists of GluK2 receptor. The compounds concerned are derivatives of indole and carbazole and are the second reported series of non-competitive antagonists of the GluK2 receptor (the first one was also published by our group). The activity of the indole derivatives is in the micromolar range, as in the case of the first series of non-competitive GluK2 receptor antagonists. We have found that designed carbazole derivatives are devoid of activity. Active indole derivatives interact with the transduction domain of the GluK2 receptor, i.e., the domain which links the transmembrane region of the receptor with the agonist-binding domain. The binding pocket is situated within one receptor subunit.

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Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors

Cited by 13 publications

References 29 publications

Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes

Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes

Thermal and spectroscopic studies of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles as non-competitive antagonists of GluK1/GluK2 receptors

Synthesis and molecular docking of novel non-competitive antagonists of GluK2 receptor

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