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Background: Irritable bowel syndrome (IBS) has a major negative influence on quality of life, causing cramps, stomach pain, bloating, constipation, etc. Antispasmodics have varying degrees of efficacy. Mebeverine, for example, works by controlling bowel movements and relaxing the muscles of the intestines but has side effects. Therefore, more efficient medication is required. Methods: In the current study, we investigated the synthesis of novel mebeverine analogs and determined ex vivo their spasmolytic and in vitro and ex vivo anti-inflammatory properties. The ability to influence both contractility and inflammation provides a dual-action approach, offering a comprehensive solution for the prevention and treatment of both conditions. Results: The results showed that all the compounds have better spasmolytic activity than mebeverine and good anti-inflammatory potential. Among the tested compounds, 3, 4a, and 4b have been pointed out as the most active in all the studies conducted. To understand their mechanism of activity, molecular docking simulation was investigated. The docking analysis explained the biological activities with their calculated Gibbs energies and possibilities for binding both centers of albumin. Moreover, the calculations showed that molecules can bind also the two muscarinic receptors and interleukin-β, hence these structures would exert a positive therapeutic effect owed to interaction with these specific receptors/cytokine. Conclusions: Three of the tested compounds have emerged as the most active and effective in all the studies conducted. Future in vivo and preclinical experiments will contribute to the establishment of these novel mebeverine derivatives as potential drug candidates against inflammatory diseases in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

The synthesized compound 1-(2-chlorophenyl) 6-7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (DIQ) was investigated as a biological agent. Its potential to affect muscle contractility was predicted through in silico PASS analysis. Based on the in silico analysis, its capabilities were experimentally investigated. The study aimed to investigate the effects of DIQ on the ex vivo spontaneous contractile activity (CA) of smooth muscle (SM) tissue. DIQ was observed to reduce the strength of Ca2+-dependent contractions in SM preparations (SMP), possibly by increasing cytosolic Ca2+ levels through the activation of a voltage-gated L-type Ca2+ channel. DIQ potently affected calcium currents by modulating the function of muscarinic acetylcholine receptors (mAChRs) and 5-hydroxytryptamine (5-HT) receptors at a concentration of 50 μM. Immunohistochemical tests showed a 47% reduction in 5-HT2A and 5-HT2B receptor activity in SM cells and neurons in the myenteric plexus (MP), further confirming the effects of DIQ. Furthermore, a significant inhibition of neuronal activity was observed when the compound was co-administered with 5-HT to SM tissues. The conducted experiments confirm the ability of the isoquinoline analog to act as a physiologically active molecule to control muscle contractility and related physiological processes. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain or discomfort. Mebeverine is an antispasmodic that has been widely used in clinical practice to relieve the symptoms of IBS. However, its systemic use usually leads to side effects. Therefore, the current paper aimed to synthesize more effective medicines for IBS treatment. We used ring opening of isatoic anhydride for the synthesis in reaction with 2-phenylethylamine. In silico simulation predicted spasmolytic activity for 2-amino-N-phenethylbenzamides. The newly synthesized compounds demonstrated a relaxation effect similar to mebeverine but did not affect the serotonin or Ca2+-dependent signaling pathway of contractile activity (CA) in contrast. Having in mind the anti-inflammatory potential of antispasmodics, the synthesized molecules were tested in vitro and ex vivo for their anti-inflammatory effects. Four of the newly synthesized compounds demonstrated very good activity by preventing albumin denaturation compared to anti-inflammatory drugs/agents well-established in medicinal practice. The newly synthesized compounds also inhibited the expression of interleukin-1β and stimulated the expression of neuronal nitric oxide synthase (nNOS), and, consequently, nitric oxide (NO) synthesis by neurons of the myenteric plexus. This characterizes the newly synthesized compounds as biologically active relaxants, offering a cleaner and more precise application in pharmacological practice, thereby enhancing their potential therapeutic value. [ABSTRACT FROM AUTHOR]

This article concerns the spasmolytic activities of some novel 1,3-disubstituted 3,4-dihydroisoquinolines. These compounds can be evaluated as potential therapeutic candidates according to Lipinski's rule of five, showing high gastrointestinal absorption and the ability to cross the blood–brain barrier, which is a very important parameter in the drug discovery processes. In silico simulation predicted smooth muscle relaxant activity for all the compounds. Since smooth muscle contractile failure is a characteristic feature of many disorders, in the current paper, we concentrate on the parameters of the spontaneous contractile responses of smooth muscle (SM) cells compared to the well-known drug mebeverine. Two of the newly synthesized substances can be identified as essential modulating regulators and potentially used as therapeutic molecules. One of these molecules also showed significant DPPH antioxidant activity compared to rutin. [ABSTRACT FROM AUTHOR]

Chronic, multifactorial illnesses of the gastrointestinal tract include inflammatory bowel diseases. One of the greatest methods for regulated medicine administration in a particular region of inflammation is the nanoparticle system. Silver nanoparticles (Ag NPs) have been utilized as drug delivery systems in the pharmaceutical industry. The goal of the current study is to synthesize drug-loaded Ag NPs using a previously described 3-methyl-1-phenylbutan-2-amine, as a mebeverine precursor (MP). Methods: A green, galactose-assisted method for the rapid synthesis and stabilization of Ag NPs as a drug-delivery system is presented. Galactose was used as a reducing and capping agent forming a thin layer encasing the nanoparticles. Results: The structure, size distribution, zeta potential, surface charge, and the role of the capping agent of drug-loaded Ag NPs were discussed. The drug release of the MP-loaded Ag NPs was also investigated. The Ag NPs indicated a very good drug release between 80 and 85%. Based on the preliminary results, Ag NPs might be a promising medication delivery system for MP and a useful treatment option for inflammatory bowel disease. Therefore, future research into the potential medical applications of the produced Ag NPs is necessary. [ABSTRACT FROM AUTHOR]