3D Reconstruction of a Full-Size GABAB Receptor

Nyporko, A. Yu.; Naumenko, A. M.; Golius, Anastasiia; Tsymbaliuk, O. V.; Shapoval, L. M.; Davidovska, T. L.

doi:10.1007/s11062-016-9544-3

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…The affinity value of this compound pKB was 7.28 ± 0.70 and IC50 = 5.25•10 -8 M. It has also been established that compound 7 does not significantly affect the nicotinic cholinergic receptors and adrenergic receptors of the respiratory tract in rats. Using a phospholipase C inhibitor (U-73122) and blockers of inositol 1,4,5-trisphosphate-sensitive (2-APB) and ryanodine-sensitive (caffeine) Ca 2+ channels of the sarcoplasmic reticulum, it was demonstrated that the aforementioned compounds act on the intracellular signaling cascade through M3 type muscarinic cholinergic receptors [28][29][30][31]. Previously, we established [19] that for the known non-selective competitive antagonist of muscarinic cholinergic receptors, ipratropium bromide, the slope of the Schild regression line was 0.79 ± 0.07 (coefficient of determination R 2 = 0.99), and the affinity value pKB was 9.14 ± 0.62 with an IC50 of 7.24•10 -10 M. Therefore, compound 7 has a lower affinity and is characterized by higher EC50 values compared to ipratropium bromide.…”

Section: Resultsmentioning

confidence: 99%

New promising agents against COPD and asthma among the amides of 1-oxo-3-phenyl-isochroman-6-carboxylic acid

Nyporko,

Tsymbalyuk,

Voiteshenko

et al. 2023

Biophysical Bulletin

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Background: Bronchodilators, which are compounds that can relax airway smooth muscle, are perhaps the most important component of combination therapy for chronic obstructive pulmonary disease, one of the most common non-communicable diseases in the world, which is the second most lethal disease after cardiovascular disease. Unfortunately, current clinical bronchodilators, whose activity is mediated by their interaction with muscarinic acetylcholine receptors, have side effects (up to myocardial infarction) due to their cross-affinity for different types of these receptors, including those prevalent in the heart muscle. Objectives: The aim of this work is to search/develop compounds — effective bronchodilators capable of selectively inhibiting type 3 muscarinic acetylcholine receptors (M3 receptors), predominantly present in smooth muscles and not characteristic of cardiomyocytes. Materials and Methods: High-throughput virtual screening of a collection of 150,000 compounds was conducted on the spatial structure of the M3 receptor, reconstructed in our previous studies. The effect of substances on contractile activity was investigated using tensometry in isometric mode on multicellular tracheal preparations. Antagonistic activity and type of inhibition were determined against the background of acetylcholine application (concentration range 10-10–10-3 M). To establish the affinity value of the compound-antagonist, the Schild regression equation was used. Results: Based on virtual screening data, a series of compounds — amides of 1-oxo-3-phenyl-iso-chroman-6-carboxylic acid — were selected for biological testing. For two of these compounds (Compounds 1 and 7), the ability to selectively inhibit M3 receptors was demonstrated. Specifically, the affinity value pKB for Compound 1 was 7.28 ± 0.70, with an IC50 of 5.25·10-8 M. A critically important advantage of this compound is its ability, at equal concentrations, to more effectively inhibit signal transmission through M3 receptors compared to ipratropium bromide — a clinical cholinergic receptor inhibitor. Conclusions: The sufficient effectiveness of inhibition and significantly increased selectivity of the studied compounds specifically towards M3 receptors provide strong grounds to consider these compounds as promising precursors of new generation cholinolytic drugs with targeted action on M3-type cholinergic receptors.

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Section: Resultsmentioning

confidence: 99%

New promising agents against COPD and asthma among the amides of 1-oxo-3-phenyl-isochroman-6-carboxylic acid

Nyporko,

Tsymbalyuk,

Voiteshenko

et al. 2023

Biophysical Bulletin

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“…The spatial structure of the extracellular part of GABA B1a subunit (15-592 amino acid residues) was obtained via the molecular simulation of the full-size GABA B receptor, that was conducted in our previous studies (Fig. 3, А) [19]. The threedimensional structure of the ТіО 2 particle (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The construction of the spatial structure of full-size GABA B receptor (Fig. 2), the investigation of its molecular dynamics and estimation of the energy of nonvalent interactions in the model of the complex of GABA B receptor with lipid bilayer membrane was performed in our previous work [19].…”

Section: Figmentioning

confidence: 99%

Molecular docking of nanosized titanium dioxide material to the extracellular part of GABAB-receptor

et al. 2016

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“…GABA is a neuromediator of both central and peripheral nervous systems [1,2,13]. Our studies [12] using the method of molecular docking of nanosized TiO 2 material to the extracellular part of GABA receptor we have determined potentially probable sites of binding nanosized TiO 2 material of different affinity and analyzed the character of bonds, stabilizing them according to their amino acid composition.…”

Section: Figmentioning

confidence: 99%

Nanosized titanium dioxide material. Modulation of spontaneous motility and gaba-dependent regulation of functions of stomach smooth muscles in vivo

et al. 2017

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Electron scanning microscopy was used to obtain the image and identify the size of TiO 2 nanoparticles. Using the tenzometric method in the isometric mode, it was estab lished that chronic effect of TiO 2 on stomach smooth muscles led to redistribution of the amplitudes of spontaneous contractions in terms of their frequencies. An increase in frequency of their contractions, decrease in the duration of contraction-relaxation cycle, the disturbance of the asymmetry of the duration of contraction-relaxation development, a reduction in Montevideo index of contractions and Alexandria index of contractions were demonstrated. It was also shown the existance of the divergence in numerical va lues of frequency amplitude complexes, TiO 2 -modified spontaneous contractive activi ty of smooth muscles of stomach and caecum. In the conditions of long-term chronic influ ence (100 days), TiO 2 removes the regulatory mechanisms of depressing a release of inhibition neuromediators from neurons of the intramural nervous interlacement, medi ated by GABA А and GABA С receptors, in smooth musc les of stomach and caecum.

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3D Reconstruction of a Full-Size GABAB Receptor

Cited by 6 publications

References 39 publications

New promising agents against COPD and asthma among the amides of 1-oxo-3-phenyl-isochroman-6-carboxylic acid

New promising agents against COPD and asthma among the amides of 1-oxo-3-phenyl-isochroman-6-carboxylic acid

Molecular docking of nanosized titanium dioxide material to the extracellular part of GABAB-receptor

Nanosized titanium dioxide material. Modulation of spontaneous motility and gaba-dependent regulation of functions of stomach smooth muscles in vivo

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