Біологічні студії (Dec 2023)

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

  • Olga Tsymbalyuk,
  • Ivan Voiteshenko,
  • Sergii Starosyla,
  • Volodymyr Bdzhola,
  • Andriy Prykhodko,
  • Tetyana Fedirko,
  • Oleksandr Savchenko,
  • Anna Bakhina,
  • Oleksii Nyporko

DOI
https://doi.org/10.30970/sbi.1704.746
Journal volume & issue
Vol. 17, no. 4
pp. 15 – 36

Abstract

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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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