An Investigation of Novel Series of 2-Thioxo-1,3-dithiol-carboxamides as Potential Antispasmodic Agents: Design, Synthesis via Coupling Reactions, Density Functional Theory Calculations, and Molecular Docking.

This study reports the synthesis of 2-thioxo-1,3-dithiol-carboxamides (TDTCAs) under mild conditions at room temperature using HBTU as a coupling agent, which significantly improved amide bond formation. The synthesized compounds were characterized using several analytical techniques, including 1H and 13C NMR spectroscopy, and HRMS, confirming their intended structures and structural integrity. A DFT computational study at the B3LYP/6-31G(d,p) level was conducted on the four synthesized compounds to compare their electronic properties and molecular structures. The results showed that these compounds demonstrated antispasmodic effects on jejunum contractions. Molecular docking revealed that compounds c and d displayed the highest docking scores on potassium and voltage-gated calcium channels and adrenergic receptors. In summary, compounds c and d exhibit antispasmodic effects, potentially blocking alpha-adrenergic receptors and calcium channels, thus providing a scientific basis for their potential use in treating gastrointestinal disorders.

2-Amino-N-Phenethylbenzamides for Irritable Bowel Syndrome Treatment.

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-1ß 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.

Myorelaxant and antispasmodic effects of the essential oil of Artemisia campestris L., and the molecular docking of its major constituents with the muscarinic receptor and the L-type voltage-gated Ca2+channel.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrointestinal disorders are among the most common diseases that cause discomfort to people who are affected. In Morocco, aromatic and medicinal plants are widely used to calm these pains and eliminate their symptoms. Among these plants, Artemisia campestris L. which is used in eastern Morocco to treat digestive system problems. AIM OF THE STUDY: Our study aimed to experimentally verify the traditional use of this plant by evaluating the myorelaxant and antispasmodic effects of the essential oil of Artemisia campestris L. (EOAc). MATERIALS AND METHODS: Gas Chromatography-Mass Spectrometry analysis (GC-MS) was performed to identify the compounds present in the EOAc. Then, these molecules were subjected to the in silico study for molecular docking. The myorelaxant and antispasmodic evaluation of the EOAc were tested in vitro on an isolated rabbit and rat jejunum mounted on an organ bath. Then, an isotonic transducer connected to an amplifier recorded the graph related to intestinal contractility. RESULTS: GC-MS analysis of the essential oil of Artemisia campestris L. showed the presence of m-Cymene (17.308%), Spathulenol (16.785%), ß Pinene (15.623%), α Pinene (11.352%), α.-Campholenal (8.848%) as main constituents. The EOAc gave a dose-dependent and reversible myorelaxant effect on the spontaneous contractions of jejunum isolated from rabbits, with an IC50 equal to 72.16 ± 15.93 µg/mL. This effect did not occur through adrenergic receptors. The EOAc has an antispasmodic effect on the contractions of rat jejunal induced by a medium with low (25 mM) or high concentration (75 mM) of KCl, and carbachol 10-6 M. The obtained inhibitory effects are comparable to those of a non-competitive antagonist of cholinergic receptors. The major compounds of EOAc allowed the establishment of a relationship between these phytoconstituents and the antispasmodic effect found by the EOAc. The obtained results are also supported by a docking study. CONCLUSION: The obtained results confirm favorably the use of Artemisia campestris L. in traditional Moroccan medicine for the treatment of digestive tract illness, which gives us a new route to valorize the effects obtained by a phytomedicine specific for the digestive tract.

The Detailed Pharmacodynamics of the Gut Relaxant Effect and GC-MS Analysis of the Grewia tenax Fruit Extract: In Vivo and Ex Vivo Approach.

The study was performed to assess and rationalize the traditional utilization of the fruit part of Grewia tenax (G. tenax). The phytoconstituents present in the methanolic extract were analyzed using Gas-Chromatography-Mass Spectroscopy (GC-MS), while the anti-diarrheal activity was investigated in the Swiss albino mice against castor oil-provoked diarrhea in vivo. The antispasmodic effect and the possible pharmacodynamics of the observed antispasmodic effect were determined in an isolated rat ileum using the organ bath setup as an ex vivo model. GC-MS findings indicate that G. tenax is rich in alcohol (6,6-dideutero-nonen-1-ol-3) as the main constituent (20.98%), while 3-Deoxy-d-mannoic lactone (15.36%) was detected as the second major constituents whereas methyl furfural, pyranone, carboxylic acid, vitamin E, fatty acid ester, hydrocarbon, steroids, sesquiterpenes, phytosterols, and ketones were verified as added constituents in the methanolic extract. In mice, the orally administered G. tenax inhibited the diarrheal episodes significantly (p < 0.05) at 200 mg/kg (40% protection), and this protection was escalated to 80% with the next higher dose of 400 mg/kg. Loperamide (10 mg/kg), a positive control drug, imparted 100% protection, whereas no protection was shown by saline. In isolated rat ileum, G. tenax completely inhibited the carbamylcholine (CCh; 1 µM) and KCl (high K+; 80 mM)-evoked spasms in a concentrations-mediated manner (0.03 to 3 mg/mL) by expressing equal potencies (p > 0.05) against both types of evoked spasms, similar to papaverine, having dual inhibitory actions at phosphodiesterase enzyme (PDE) and Ca2+ channels (CCB). Similar to papaverine, the inhibitory effect of G. tenax on PDE was further confirmed indirectly when G. tenax (0.1 and 0.3 mg/mL) preincubated ileal tissues shifted the isoprenaline-relaxation curve towards the left. Whereas, pre-incubating the tissue with 0.3 and 1 mg/mL of G. tenax established the CCB-like effect by non-specific inhibition of CaCl2−mediated concentration-response curves towards the right with suppression of the maximum peaks, similar to verapamil, a standard CCB. Thus, the present investigation revealed the phytochemical constituents and explored the detailed pharmacodynamic basis for the curative use of G. tenax in diarrhea and hyperactive gut motility disorders.

The Antispasmodic Effect of Warionia saharae Essential Oil in Experimental Models and its Mechanism of Action.

With several medicinal and aromatic species, the Asteraceae family is one of the largest angiosperm families. The genus Warionia is represented in this family by only one species, Warionia saharae. In Moroccan traditional medicine, this species is widely used to treat gastrointestinal problems. Essential oil of this plant (EoWs) was studied for possible myorelaxant and antispasmodic activities to rationalize some of the traditional uses. In this investigation, hydrodistillation was used to obtain the essential oil from the aerial part of the dry plant extract (EoWs), which was then analyzed using gas chromatography coupled to mass spectrometry (GC/MS). The major compounds identified in the EoWs are nerolidyl acetate (21.44%), ß-Eudesmol (19.47%), linalool (16.48%), 1-terpinene-4-ol (10.93%), and cineole (5.34%). EoWs is relatively safe in the case of acute intake up to 2 g/kg body weight of albino mice. The effect of EoWs on intestinal relaxation was investigated using rabbit and rat jejunal smooth muscle. We have noticed that EoWs produce a myorelaxation on basal rabbit jejunum's contractions in a concentration-dependent manner with a maximal effect at 30 µg/mL. This myorelaxation was not dependent on adrenergic receptors. When the rat jejunums were pre-contracted with 25 mM KCl or 10 µM Carbachol (CCh), EoWs had an antispasmodic action with an IC50 values of 15.76 ± 0.37 and 12.04 ± 0.30 µg/mL, respectively. Preliminary results showed that it is probable that our plant might act directly through the NO and guanylate cyclase signaling pathway and on muscarinic but not nicotinic receptors. The results reveal that the Essential oil of W. saharae appears to have an impact on intestinal relaxation in vitro conditions. This finding lends credence to the traditional usage of this plant to treat intestinal disorders.

GC-MS Analysis and In Vivo and Ex Vivo Antidiarrheal and Antispasmodic Effects of the Methanolic Extract of Acacia nilotica.

This present study evaluated and rationalized the medicinal use of the fruit part of Acacia nilotica methanolic extract. The phytochemicals were detected using gas chromatography−mass spectrometry (GC−MS) while the in vivo antidiarrheal test was done using Swiss albino mice. To determine the details of the mechanism(s) involved in the antispasmodic effect, isolated rat ileum was chosen using different ex vivo assays by maintaining a physiological environment. GC−MS results showed that A. nilotica contained pyrogallol as the major polyphenol present (64.04%) in addition to polysaccharides, polyphenol, amino acid, steroids, fatty acid esters, and triterpenoids. In the antidiarrheal experiment, A. nilotica inhibited diarrheal episodes in mice significantly (p < 0.05) by 40% protection of mice at 200 mg/kg, while 80% protection was observed at 400 mg/kg by the orally administered extract. The highest antidiarrheal effect was observed with loperamide (p < 0.01), used as a control drug. In the ex vivo experiments, A. nilotica inhibited completely in increasing concentrations (0.3 to 10 mg/mL) the carbachol (CCh; 1 µM) and high K+ (80 mM)-evoked spasms in ileum tissues at equal potencies (p > 0.05), similar to papaverine, a dual inhibitor of the phosphodiesterase enzyme (PDE) and Ca++ channels. The dual inhibitory-like effects of A. nilotica on PDE and Ca++ were further validated when A. nilotica extract (1 and 3 mg/mL)-pre-incubated ileum tissues potentiated and shifted isoprenaline relaxation curves towards lower doses (leftward), similar to papaverine, thus confirming the PDE inhibitory-like mechanism whereas its CCB-like effect of the extract was confirmed at 3 and 5 mg/mL by non-specific inhibition of CaCl2-mediated concentration response curves towards the right with suppression of the maximum peaks, similar to verapamil, used as standard CCB. Thus, this study characterized the chemical composition and provides mechanistic support for medicinal use of A. nilotica in diarrheal and hyperactive gut motility disorders.

In Silico and Ex Vivo Studies on the Spasmolytic Activities of Fenchone Using Isolated Guinea Pig Trachea.

Fenchone is a bicyclic monoterpene found in a variety of aromatic plants, including Foeniculum vulgare and Peumus boldus, and is used in the management of airways disorders. This study aimed to explore the bronchodilator effect of fenchone using guinea pig tracheal muscles as an ex vivo model and in silico studies. A concentration-mediated tracheal relaxant effect of fenchone was evaluated using isolated guinea pig trachea mounted in an organ bath provided with physiological conditions. Sustained contractions were achieved using low K+ (25 mM), high K+ (80 mM), and carbamylcholine (CCh; 1 µM), and fenchone inhibitory concentration-response curves (CRCs) were obtained against these contractions. Fenchone selectively inhibited with higher potency contractions evoked by low K+ compared to high K+ with resultant EC50 values of 0.62 mg/mL (0.58-0.72; n = 5) and 6.44 mg/mL (5.86-7.32; n = 5), respectively. Verapamil (VRP) inhibited both low and high K+ contractions at similar concentrations. Pre-incubation of the tracheal tissues with K+ channel blockers such as glibenclamide (Gb), 4-aminopyridine (4-AP), and tetraethylammonium (TEA) significantly shifted the inhibitory CRCs of fenchone to the right towards higher doses. Fenchone also inhibited CCh-mediated contractions at comparable potency to its effect against high K+ [6.28 mg/mL (5.88-6.42, n = 4); CCh] and [6.44 mg/mL (5.86-7.32; n = 5); high K+]. A similar pattern was obtained with papaverine (PPV), a phosphodiesterase (PDE), and Ca2+ inhibitor which inhibited both CCh and high K+ at similar concentrations [10.46 µM (9.82-11.22, n = 4); CCh] and [10.28 µM (9.18-11.36; n = 5); high K+]. However, verapamil, a standard Ca2+ channel blocker, showed selectively higher potency against high K+ compared to CCh-mediated contractions with respective EC50 values of 0.84 mg/mL (0.82-0.96; n = 5) 14.46 mg/mL (12.24-16.38, n = 4). The PDE-inhibitory action of fenchone was further confirmed when its pre-incubation at 3 and 5 mg/mL potentiated and shifted the isoprenaline inhibitory CRCs towards the left, similar to papaverine, whereas the Ca2+ inhibitory-like action of fenchone pretreated tracheal tissues were authenticated by the rightward shift of Ca2+ CRCs with suppression of maximum response, similar to verapamil, a standard Ca2+ channel blocker. Fenchone showed a spasmolytic effect in isolated trachea mediated predominantly by K+ channel activation followed by dual inhibition of PDE and Ca2+ channels. Further in silico molecular docking studies provided the insight for binding of fenchone with Ca2+ channel (-5.3 kcal/mol) and K+ channel (-5.7), which also endorsed the idea of dual inhibition.

The Spasmolytic, Bronchodilator, and Vasodilator Activities of Parmotrema perlatum Are Explained by Anti-Muscarinic and Calcium Antagonistic Mechanisms.

Parmotremaperlatum is traditionally used in different areas of Pakistan to treat gastrointestinal, respiratory, and vascular diseases. This study evaluates the underlying mechanisms for traditional uses of P. perlatum in diarrhea, asthma, and hypertension. In vitro pharmacological studies were conducted using isolated jejunum, trachea, and aortic preparations, while the cytotoxic study was conducted in mice. Crude extract of P. perlatum(Pp.Cr), comprising appreciable quantities of alkaloids and flavonoids, relaxed spontaneously contracting jejunum preparation, K+ (80 mM)-induced, and carbachol (1 µM)-induced jejunum contractions in a concentration-dependent manner similar to dicyclomine and dantrolene. Pp.Cr showed a rightward parallel shift of concentration-response curves (CRCs) of Cch after a non-parallel shift similarto dicyclomine and shifted CRCs of Ca+2 to rightward much likeverapamil and dantrolene, demonstrating the coexistence of antimuscarinic and Ca+2 antagonistic mechanism. Furthermore, Pp.Cr, dicyclomine, and dantrolene relaxed K+ (80 mM)-induced and Cch (1 µM)-induced tracheal contractions and shifted rightward CRCs of Cch similar to dicyclomine, signifying the dual blockade. Additionally, Pp.Cr also relaxed the K+ (80 mM)-induced and phenylephrine (1 µM)-induced aortic contraction, similarly to verapamil and dantrolene, suggesting Ca+2 channel antagonism. Here, we explored for the first time thespasmolytic and bronchodilator effects of Pp.Crand whether they maybe due to the dual blockade of Ca+2 channels and muscarinic receptors, while the vasodilator effect might be owing to Ca+2 antagonism. Our results provide the pharmacological evidence that P. perlatum could be a new potential therapeutic option to treat gastrointestinal, respiratory, and vascular diseases. Hence, there is a need for further research to explore bioactive constituent of P. perlatum as well as further investigation by suitable experimental models are required to further confirm the importance and usefulness of P. perlatum in diarrhea, asthma, and hypertension treatment.

Spasmolytic Effects of Aphanizomenon Flos Aquae (AFA) Extract on the Human Colon Contractility.

The blue-green algae Aphanizomenon flos aquae (AFA), rich in beneficial nutrients, exerts various beneficial effects, acting in different organs including the gut. Klamin® is an AFA extract particularly rich in ß-PEA, a trace-amine considered a neuromodulator in the central nervous system. To date, it is not clear if ß-PEA exerts a role in the enteric nervous system. The aims of the present study were to investigate the effects induced by Klamin® on the human distal colon mechanical activity, to analyze the mechanism of action, and to verify a ß-PEA involvement. The organ bath technique, RT-PCR, and immunohistochemistry (IHC) were used. Klamin® reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions. EPPTB, a trace-amine receptor (TAAR1) antagonist, significantly antagonized the inhibitory effects of both Klamin® and exogenous ß-PEA, suggesting a trace-amine involvement in the Klamin® effects. Accordingly, AphaMax®, an AFA extract containing lesser amount of ß-PEA, failed to modify colon contractility. Moreover, the Klamin® effects were abolished by tetrodotoxin, a neural blocker, but not by L-NAME, a nitric oxide-synthase inhibitor. On the contrary methysergide, a serotonin receptor antagonist, significantly antagonized the Klamin® effects, as well as the contractility reduction induced by 5-HT. The RT-PCR analysis revealed TAAR1 gene expression in the colon and the IHC experiments showed that 5-HT-positive neurons are co-expressed with TAAR1 positive neurons. In conclusion, the results of this study suggest that Klamin® exerts spasmolytic effects in human colon contractility through ß-PEA, that, by activating neural TAAR1, induce serotonin release from serotoninergic neurons of the myenteric plexus.

Antispasmodic Effect of Asperidine B, a Pyrrolidine Derivative, through Inhibition of L-Type Ca2+ Channel in Rat Ileal Smooth Muscle.

Antispasmodic agents are used for modulating gastrointestinal motility. Several compounds isolated from terrestrial plants have antispasmodic properties. This study aimed to explore the inhibitory effect of the pyrrolidine derivative, asperidine B, isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, on spasmodic activity. Isolated rat ileum was set up in an organ bath. The contractile responses of asperidine B (0.3 to 30 µM) on potassium chloride and acetylcholine-induced contractions were recorded. To investigate its antispasmodic mechanism, CaCl2, acetylcholine, Nω-nitro-l-arginine methyl ester (l-NAME), nifedipine, methylene blue and tetraethylammonium chloride (TEA) were tested in the absence or in the presence of asperidine B. Cumulative concentrations of asperidine B reduced the ileal contraction by ~37%. The calcium chloride and acetylcholine-induced ileal contraction was suppressed by asperidine B. The effects of asperidine B combined with nifedipine, atropine or TEA were similar to those treated with nifedipine, atropine or TEA, respectively. In contrast, in the presence of l-NAME and methylene blue, the antispasmodic effect of asperidine B was unaltered. These results suggest that the antispasmodic property of asperidine B is probably due to the blockage of the L-type Ca2+ channel and is associated with K+ channels and muscarinic receptor, possibly by affecting non-selective cation channels and/or releasing intracellular calcium.

In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels.

The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.

Pharmacological and computational evaluation of fig for therapeutic potential in hyperactive gastrointestinal disorders.

BACKGROUND: Ficus palmata (Fig), are distributed in different parts of the world, and are used in traditional medicine to treat various ailments including inflammation, tumor, epilepsy, jaundice, influenza and bacillary dysentery. The present study aimed to evaluate the antidiarrheal, antisecretary, antispasmodic, antiulcer and anti motility properties of Ficus palmata. METHODS: In-vivo, in-vitro and in-silico techniques were used to investigate various gastrointestinal effects of Ficus palmata. Antidiarrheal, antisecretary, antispasmodic, antiulcer, anti motility and molecular docking were performed using castor oil induced diarrhea and fluid accumulation, isolated tissue preparations, ethanol-HCl induced ulcer assay, charcoal meal transit time and Auto Doc Vina. RESULTS: Ficus palmata crude extract (Fp.Cr) exhibited protection against castor oil-induced diarrhea in mice and dose-dependently inhibited intestinal fluid secretions. Fp.Cr caused relaxation of spontaneous and K+ (80 Mm)-induced contractions in isolated rabbit jejunum preparations. It showed protective effect against gastric ulcers induced by ethanol-hydrochloric acid in rats. Fp.Cr reduced distance travelled by charcoal meal in the gastrointestinal transit model in mice. The plant constituents: psoralenoside and bergapten showed high binding affinities (E-value ≥ - 6.5 Kcal/mol) against histaminergic H1, calmodulin and voltage gated L-type calcium channels, while showed moderate affinities (E-value ≥7 Kcal/mol) against dopaminergic D2, adrenergic α1, muscranic M3, mu-opioid, whereas revealed lower affinities (E-value ≥9.5 Kcal/mol) vs. muscranic M1, histaminergic H2 and H+/K+ ATPase pump. Germanicol acetate and psoralene exhibited weak affinities against aforementioned targets. CONCLUSION: This study reveals that Ficus palmata possesses anti-diarrheal, anti-secretory, anti-spasmodic, anti-motility and anti-ulcer activities. The various constituents reveal different binding affinities against target proteins, which mediate the gastrointestinal functions.

Antispasmodic Activity of Prenylated Phenolic Compounds from the Root Bark of Morus nigra.

Black mulberry is a widely acknowledged ancient traditional medicine. Its extract and constituents have been reported to exert various bioactivities including antimicrobial, hypotensive, analgesic etc. effects. While black mulberry preparations are also used as antispasmodic agents in folk medicine, no related studies are available on its isolated constituents. Through an extensive chromatographic purification, seven phenolic compounds were isolated from the methanol extract of Morus nigra root bark, including morusin (1), kuwanon U (2), kuwanon E (3), moracin P (4), moracin O (5), albanol A (6), and albanol B (7). A complete NMR signal assignment of moracin P and O was achieved, and related literature errors confusing the identity of moracin derivatives are hereby clarified. Compounds 2, 5 and 7 were identified as strong antispasmodic agents on isolated rat ileum and tracheal smooth muscles, while compound 3, a methoxy derivative of 2, was inactive. Moracin O (5) inhibited the ileal and tracheal smooth muscle contractions with Emax values of 85% and 302 mg, respectively. Those actions were superior as compared with papaverine. Our findings demonstrate that prenylated arylbenzofurans, geranylated flavonoids and Diels-Alder adducts from Morus nigra are valuable antispasmodic agents. Compounds 2, 5 and 7 are suggested as marker compounds for quality control of antispasmodic mulberry preparations. Moracin O (5) is a new lead compound for related drug development initiatives.

Butyrlycholine esterase inhibitory activity and effects of extracts (fruit, bark and leaf) from Zanthoxylum armatum DC in gut, airways and vascular smooth muscles.

BACKGROUND: Fruit, bark and leaves of Zanthoxylum armatum DC are popular remedies for gastrointestinal, cardiovascular and respiratory disorders in the subcontinent traditional practices. The aim of the study was to individually probe the profile of methanol extracts from three different parts of Zanthoxylum armatum. METHODS: The ex-vivo muscle relaxant effects of extracts were assessed in the isolated intestine, trachea and thoracic aortic rings and were compared with the positive controls and CRC were constructed. The anti-diarrheal effect of extracts was evaluated in mice by inducing diarrhea with castor oil. The extracts were also studied for acute toxicity and butyrylcholine esterase inhibition. RESULTS: The extracts from fruit, bark and leaves of Z. armatum showed inhibitory effect against the butyrylcholine esterase enzyme with percent inhibition of 50.75 ± 1.23, 82.57 ± 1.33, and 37.52 ± 1.11respectively, compared to standard serine (IC50: 0.04 ± 0.001 µmol/L). The fruit and bark extracts provided 75, and 52% diarrheal protection, compared to verapamil (96%). In isolated rabbit jejunum strips, increasing addition of the extracts inhibited the spontaneous and high K+ precontractions with EC50 values of 0.71 and 3 mg/mL for fruit, EC50 values of 0.61 and 0.5 mg/mL for bark, EC50 0.81 and 3.1 mg/mL for leaves, like verapamil. The extracts induced a concentration-dependent relaxation of the carbachol (1 µM) and high K+ (80 mM) precontractions with EC50 values of 2.4 and 0.9 mg/mL for fruit, EC50 values of 1.2 and 3 for leaves. The bark extract was equipotent against both contractions with EC50 3.1 and 0.7 mg/mL, respectively. In the aortic rings, the fruit extract completely relaxed the phenylephrine (1 µM)-induced contractions with (EC50 value = 0.8 mg/ml) and a partial inhibition of high K+ induced contractions. The leaves extract completely relaxed the aortic contractions with (EC50 values = 1.0 and 8.5 mg/ml). The extracts caused no acute toxicity up to 3 g/kg dose. CONCLUSIONS: The experiments revealed that the extracts of aerial parts of Z. armatum have antidiarrheal properties in vivo and showed spasmolytic effect in intestinal and tracheal preparations with possible mechanism involving the blockage of Ca++ channels. These experiments provide enough justification for use of this plant in ethnomedicine in diarrhea, gut and bronchial spasms.

Review: Bioactive constituents form Buddleja species.

Present review discuss the reported work on structures, origins and the potent biologically active natural products isolated from Genus Buddleja, which is known for having many important pharmacologically active substances. The Genus Buddleja have more than 100 species, many of them are distributed in Mediterranean and Asian regions. A very small number of common species of the Genus in majority of fruiting plants have been investigated for their biological potential. So for, isolation of about 153 or more new/novel chemical substances have been reported. Purposes of the review is to discuss the structurally established and pharmacologically significant natural substances from wide variety of different species of this genus. Traditionally, species of the genus are reported to be used for healing, treatment of liver diseases, bronchial complaints, preventing several other diseases by exhibiting diuretic properties, sedative functions, analgesic potential, antirheumatic actions, antimicrobial activities, anti hyperglycemic functions and antioxidant properties. In this review we will describe recently established medicinal chemistry aspects and complete list of phytoconstituents as well as their sources and reference.

Antispasmodic Effect of Essential Oils and Their Constituents: A Review.

The antispasmodic effect of drugs is used for the symptomatic treatment of cramping and discomfort affecting smooth muscles from the gastrointestinal, billiary or genitourinary tract in a variety of clinical situations.The existing synthetic antispasmodic drugs may cause a series of unpleasant side effects, and therefore the discovery of new molecules of natural origin is an important goal for the pharmaceutical industry. This review describes a series of recent studies investigating the antispasmodic effect of essential oils from 39 plant species belonging to 12 families. The pharmacological models used in the studies together with the mechanistic discussions and the chemical composition of the essential oils are also detailed. The data clearly demonstrate the antispasmodic effect of the essential oils from the aromatic plant species studied. Further research is needed in order to ascertain the therapeutic importance of these findings.

Basal and Spasmolytic Effects of a Hydroethanolic Leaf Extract of Melissa officinalis L. on Intestinal Motility: An Ex Vivo Study.

Melissa officinalis L. (lemon balm) has been used for decades with symptomatic benefits in patients with digestive disorders. However, very little is known on the effects of M. officinalis on the gastrointestinal (GI) tract. In this study, the basal and spasmolytic properties of a hydroethanolic leaf extract (HLE) of M. officinalis were assessed ex vivo on different segments of the GI tract of mice after phytochemical characterization of the extract. M. officinalis HLE had site- and dose-dependent effects on the contractile activity of the GI tract, the motility response being impacted in the jejunum and ileum but not in the antrum and colon. The observed effects could be caused by the phenolic compounds (mainly rosmarinic acid) detected in the extract.

5-Oxo-hexahydroquinoline: an attractive scaffold with diverse biological activities.

5-Oxo-hexahydroquinoline (5-oxo-HHQ) represents a biologically attractive fused heterocyclic core. Various synthetic analogs of 5-oxo-HHQ have been synthesized and assessed for different biological activities. Some derivatives have exhibited myorelaxant, analgesic, anticancer, antibacterial, antifungal, antitubercular, antimalarial, antioxidant, anti-inflammatory, multidrug resistance reversal, anti-Alzheimer, neuroprotective, antidiabetic, antidyslipidemic and antiosteoporotic activities. This review provides a comprehensive report regarding the preparation and pharmacological characterization of 5-oxo-HHQ derivatives that have been reported so far. This information will be beneficial for medicinal chemists in the field of drug discovery to design and develop new and potent therapeutical agents bearing the 5-oxo-HHQ nucleus.

Design, synthesis and in vitro evaluation of a Dopa-organoboron compound that acts as a bladder relaxant through non-catecholamine receptors.

Bladder relaxation through drug administration is an interesting topic in medicinal and combinatorial chemistry. In fact, compounds targeting catecholamine receptors [dopamine receptors and beta-adrenergic receptors (ßAR) expressed in the bladder] are among the compounds commonly employed for this purpose. In particular, recent investigations have tended to focus on the ß3-adrenoceptor (ß3AR) as a target in the treatment of urinary incontinence and other disorders. However, organoboron compounds have been suggested as potent and efficient agents on these drug targets. In this work, through a docking study, we identified the parameters that induce a theoretical improvement in the affinity and activity of the organoboron compounds on the catecholamine receptors expressed in the bladder. Then, the identified potential drug, a boron-containing dopa-derivative named DPBX-L-Dopa, was synthesized and characterized. This compound induces a relaxation on the smooth muscle of the rat bladder, behaving as a weak relaxant compared to isoproterenol but with similar efficacy to BRL377, a selective ß3AR agonist. However, unexpectedly, this effect was not blocked by propranolol or haloperidol at the concentrations at which they are able to block the catecholamine receptors in bladder tissue. In view of these results, the effect of DPBX-L-Dopa compound on the alpha 1 adrenergic receptors (α1AR) of aorta of the rats was also explored; however, no response of the tissue to this compound was obtained. The possible mechanisms of the action of this compound were explored and are discussed further.

Myorelaxant Activity of essential oil from Origanum majorana L. on rat and rabbit.

ETHNOPHARMACOLOGICAL RELEVANCE: Origanum majorana L. (Lamiaceae) was usually used in Moroccan folk medicine to treat infantile colic and abdominal discomfort. MATERIALS AND METHODS: The essential oil from the aerial part of the dry Origanum majorana L. (EOOM) was obtained through hydro distillation and analyzed by gas chromatography/mass spectrometry (GC/MS). The effect of EOOM on muscle relaxation was measured on rabbit and rat intestinal smooth muscle mounted in an isotonic transducer. RESULTS: 1) The main compounds obtained from the aqueous extract of this plant were alpha Terpineol, L-terpinen-4-ol and Beta.-Linalool. 2) EOOM inhibited in a concentration-dependent manner spontaneous contraction of rabbit jejunum, with an IC50 = 64.08 ±â€¯2.42 µg/mL. 3) In rat intestine, EOOM induced the relaxation of the tissue in concentration-dependent manner with an IC50 = 39.70 ±â€¯2.29 µg/mL when the tissue was pre-contracted with CCh 10-6 M, and 48.70 ±â€¯2.26 µg/mL when the tissue was pre-contracted with 25 mM KCl. 4) The relaxation effect induced by EOOM was more important than that obtained in the presence of atropine, hexamethonium, Nifedipine, L-NAME and Blue of methylene. CONCLUSION: the present result indicates that essential oil of Origanum majorana L. exhibit an effect on intestinal relaxation in vitro. This effect further validates the traditional use of Origanum majorana L. to treat infantile colic and abdominal discomfort.