Computer‐aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones

Nyporko, A. Yu.; Tsymbalyuk, O. V.; Voiteshenko, I. S.; Starosyla, Sergiy A.; Protopopov, M. V.; Bdzhola, Volodymyr G.

doi:10.1002/minf.202300006

Cited by 2 publications

(3 citation statements)

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“…For pharmacological testing in vitro on multicellular smooth muscle preparations of rat tracheal rings, seven most promising compoundsamides of 1-oxo-3-phenyl-isochroman-6carboxylic acid (1-7, Table 1) with predicted cholinolytic activity were selected through preliminary in silico screening. As a target for screening, the spatial structure of the M3 type cholinergic receptor, reconstructed in our previous studies [19], were used. Structure of these compounds are presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…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. However, a critically important advantage of compound 7 is its ability, at equal concentrations, to more effectively inhibit signal transmission through M3 cholinergic receptors compared to ipratropium bromide.…”

Section: Resultsmentioning

confidence: 99%

“…The predicted structure of the M3-type muscarinic acetylcholine receptor [19] was used as a target for virtual screening. Two binding sites were identified.…”

Section: Virtual Screeningmentioning

confidence: 99%

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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%

Section: Resultsmentioning

confidence: 99%

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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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8-[(4-benzylpiperazin-1-yl)methyl]-3-(2-chlorophenyl)-7-hydroxy-chromen-4-one is an activator of contractile activity of intestinal smooth muscles with reversible M2 cholinomimetic properties

Tsymbalyuk,

Voiteshenko,

Starosyla

et al. 2023

Biol. Stud.

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Background. Several pathologies (such as diabetes mellitus, Parkinson’s and Alzheimer’s diseases, multiple sclerosis, etc.) are accompanied by degeneration of cholinergic neurons, which are key regulators of the contractile function of the gastrointestinal tract walls, leading to atony and paresis. An effective strategy for normalizing the lack of contractile function of visceral SM is the use of drugs - selective agonists of muscarinic acetylcholine receptors (mAChRs) of the M2 subtype. The high similarity of the structure of the agonist-binding sites of different subtypes of mAChRs causes problems to develop selective ligands for these receptors. Nowadays, there is an urgent necessity to develop selective agonists of M2 subtype receptors as pharmacological tools for laboratory research and promising drugs. The aim of the present research was to investigate the effect of the 8-[(4-benzylpiperazin-1-yl)methyl]-3-(2-chlorophenyl)-7-hydroxy-chromen-4-one (compound 1), which was in silico predicted to bind mAChRs, on the contractile activity of rat caecum circular smooth muscle. Materials and Methods. The research was carried out on rats. The contractile activity was studied tensometrically in the isometric mode on preparations of the circular smooth muscles of the caecum of Wistar rats. The kinetic properties of individual spontaneous contractions of SM preparations were determined in accordance with the method of multivariate mechanokinetic analysis with the calculation of mechanokinetic parameters for the phases of contraction and relaxation: time (τ0, τC and τR), force (Fmax, FC and FR), velocity (VC and VR) and impulse (Imax, IC and IR). The kinetic properties of acetylcholine-induced contractions were analyzed by calculating the normalized maximum velocities of the contraction (Vnc) and relaxation (Vnr) phases. Results. It was found that compound 1 caused an increase in the amplitude of acetylcholine-induced contractions; this effect was eliminated by preincubation of SM with the mAChRs M2 subtype inhibitor AF-DX 116. It was revealed that compound 1 (0.1–50 μM) also has the ability to significantly activate the functional activity of colonic SM in a dose-dependent manner, increasing the force and frequency of spontaneous contractions, as well as their mechanokinetic parameters. It was found that the presence of compound 1 (0.1 μM) in the solution washing the smooth muscle for a long time leads to a significant increase in the amplitude and frequency of spontaneous contractions, which tends to reach a stationary mode after 40 minutes of its action. The effect of compound 1 was stable for at least an hour of application to the caecum, and was reversible and significantly eliminated by washing the SM. Conclusions. Compound 1 stimulates the contractile activity of the cecal smooth muscle and exhibits M2 cholinergic properties.

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Computer‐aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones

Cited by 2 publications

References 32 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

8-[(4-benzylpiperazin-1-yl)methyl]-3-(2-chlorophenyl)-7-hydroxy-chromen-4-one is an activator of contractile activity of intestinal smooth muscles with reversible M2 cholinomimetic properties

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