Synthesis and Antinociceptive Effect of Some Thiazole-Piperazine Derivatives: Involvement of Opioidergic System in the Activity

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.

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Long-Lasting Anti-Inflammatory and Antinociceptive Effects of Acute Ammonium Glycyrrhizinate Administration: Pharmacological, Biochemical, and Docking Studies

Molecules ◽

10.3390/molecules24132453 ◽

2019 ◽

Vol 24 (13) ◽

pp. 2453 ◽

Cited By ~ 6

Author(s):

Francesco Maione ◽

Paola Minosi ◽

Amalia Di Giannuario ◽

Federica Raucci ◽

Maria Giovanna Chini ◽

...

Keyword(s):

Animal Models ◽

Antinociceptive Effect ◽

Binding Pocket ◽

Docking Studies ◽

Prostaglandin E ◽

Single Administration ◽

Antinociceptive Effects ◽

Anti Inflammatory

The object of the study was to estimate the long-lasting effects induced by ammonium glycyrrhizinate (AG) after a single administration in mice using animal models of pain and inflammation together with biochemical and docking studies. A single intraperitoneal injection of AG was able to produce anti-inflammatory effects in zymosan-induced paw edema and peritonitis. Moreover, in several animal models of pain, such as the writhing test, the formalin test, and hyperalgesia induced by zymosan, AG administered 24 h before the tests was able to induce a strong antinociceptive effect. Molecular docking studies revealed that AG possesses higher affinity for microsomal prostaglandin E synthase type-2 compared to type-1, whereas it seems to locate better in the binding pocket of cyclooxygenase (COX)-2 compared to COX-1. These results demonstrated that AG induced anti-inflammatory and antinociceptive effects until 24–48 h after a single administration thanks to its ability to bind the COX/mPGEs pathway. Taken together, all these findings highlight the potential use of AG for clinical treatment of pain and/or inflammatory-related diseases.

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Antinociceptive Effect of Rat D-Serine Racemase Inhibitors, L-Serine-O-Sulfate, and L-Erythro-3-Hydroxyaspartate in an Arthritic Pain Model

The Scientific World JOURNAL ◽

10.1100/2012/279147 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Claudio Laurido ◽

Alejandro Hernández ◽

Teresa Pelissier ◽

Luis Constandil

Keyword(s):

Chronic Pain ◽

Aspartic Acid ◽

Antinociceptive Effect ◽

Serine Racemase ◽

Pain Model ◽

Acid Receptor ◽

Culture Cells ◽

Antinociceptive Effects ◽

Nmdar Activation

N-methyl-D-aspartic acid receptor (NMDAr) activation requires the presence of D-serine, synthesized from L-serine by a pyridoxal 5′-phosphate-dependent serine racemase (SR). D-serine levels can be lowered by inhibiting the racemization of L-serine. L-serine-O-sulfate (LSOS) and L-erythro-3-hydroxyaspartate (LEHA), among others, have proven to be effective in reducing the D-serine levels in culture cells. It is tempting then to try these compounds in their effectiveness to decrease nociceptive levels in rat arthritic pain. We measured the C-reflex paradigm and wind-up potentiation in the presence of intrathecally injected LSOS (100 μg/10 μL) and LEHA (100 μg/10 μL) in normal and monoarthritic rats. Both compounds decreased the wind-up activity in normal and monoarthritic rats. Accordingly, all the antinociceptive effects were abolished when 300 μg/10 μL of D-serine were injected intrathecally. Since noin vivoresults have been presented so far, this constitutes the first evidence that SR inhibitions lower the D-serine levels, thus decreasing the NMDAr activity and the consequent development and maintenance of chronic pain.

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Amarisolide A and pedalitin as bioactive compounds in the antinociceptive effects of Salvia circinata

Botanical Sciences ◽

10.17129/botsci.2187 ◽

2019 ◽

Vol 97 (3) ◽

pp. 355 ◽

Cited By ~ 4

Author(s):

Gabriel Fernando Moreno-Pérez ◽

María Eva González-Trujano ◽

Martha Juana Martínez-Gordillo ◽

Rubén San Miguel-Chávez ◽

Francisco Alberto Basurto-Peña ◽

...

Keyword(s):

Antinociceptive Effect ◽

Folk Medicine ◽

Gastrointestinal Diseases ◽

Antinociceptive Activity ◽

Bioactive Constituents ◽

Response Curves ◽

Reference Drug ◽

Writhing Test ◽

H Nmr ◽

Antinociceptive Effects

Background: Salvia circinata is an endemic species of Mexico used in the folk medicine of Santiago Huauclilla, Oaxaca, mainly as remedy for gastrointestinal diseases.Hypothesis: If the extracts of Salvia circinata have secondary metabolites with antinociceptive activity, then the behavior of nociception in the model of “whriting” in mice will decrease.Specie studied: Salvia circinata Cav. (Lamiaceae).Study site and years of study: Salvia circinata was collected in Santiago Huauclilla, Oaxaca, in July 2014.Methods: Firstly, the acute toxicity of S. circinata extracts was evaluated to calculate the LD50 with OECD method. Then, dose-response curves of the antinociceptive effect of S. circinata organic and aqueous extracts (1, 10, 30, 100, and 300 mg/kg) were obtained in the writhing test in mice. Furthermore, chromatographic techniques were applied to isolate the compounds and were identified by comparison of the values of 1H NMR, 13C NMR and ESIMS reported in the literature.Results: Our data showed significant antinociceptive activity in all the tested extracts. Amarisolide A and pedalitin were isolated in the ethyl acetate and methanol extracts, respectively and assayed at doses of 1, 5 and 10 mg/kg, i.p. All the compounds decreased nociception in mice in at least 50 % from a minimal dosage of 1 mg/kg, i.p. and in a similar manner than the reference drug ketorolac (1 mg/kg, i.p.).Conclusions: Our findings give evidence that Salvia circinata possesses antinociceptive activity depending on the presence of several known bioactive constituents, reinforcing its use in the Mexican traditional medicine to alleviate abdominal pain.

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2-Allylphenol Reduces IL-1β and TNF-α, Promoting Antinociception through Adenosinergic, Anti-Inflammatory, and Antioxidant Mechanisms

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1346878 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Humberto de Carvalho Aragão Neto ◽

Diogo Vilar da Fonsêca ◽

Renan Marinho Braga ◽

Marcus Tullius Scotti ◽

Terezinha Weyne Araújo Borges do Nascimento ◽

...

Keyword(s):

In Silico ◽

Antinociceptive Effect ◽

Site Investigation ◽

Docking Studies ◽

A2a Receptors ◽

Proinflammatory Mediators ◽

Reduction Activity ◽

Anti Inflammatory

2-Allylphenol (2-AP) is a synthetic phenylpropanoid, structurally related to cardanol, thymol, and ortho-eugenol. Phenylpropanoids are described in the literature as being capable of promoting biological activity. Due to the similarity between 2-AP and other bioactive phenylpropanoids, the present research aims at evaluating the antioxidant, antinociceptive, and anti-inflammatory potential of 2-AP in silico, in vitro, and in vivo. At 30 min prior to the start of in vivo pharmacological testing, administration of 2-AP (25, 50, 75, and 100 mg/kg i.p.), morphine (6 mg/kg i.p.), dexamethasone (2 mg/kg s.c.), or vehicle alone was performed. In the acetic acid-induced abdominal writhing tests, pretreatment with 2-AP significantly reduced the number of abdominal writhes, as well as decreased licking times in the glutamate and formalin tests. Investigation of the mechanism of action using the formalin model led to the conclusion that the opioid system does not participate in its activity. However, the adenosinergic system is involved. In the peritonitis tests, 2-AP inhibited leukocyte migration and reduced releases of proinflammatory mediators TNF-α and IL-1β. In vitro antioxidant assays demonstrated that 2-AP presents significant ability to sequester superoxide radicals. In silico docking studies confirmed interaction between 2-AP and the adenosine A2a receptor through hydrogen bonds with the critical asparagine 253 residues present in the active site. Investigation of 2-AP demonstrated its nociception inhibition and ability to reduce reactive oxygen species. Its interaction with A2a receptors may well be related to proinflammatory cytokines TNF-α and IL-1β reduction activity, corroborating its antinociceptive effect.

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Contribution of spinal 5-HT5A receptors to the antinociceptive effects of systemically administered cannabinoid agonist WIN 55,212-2 and morphine

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0567 ◽

2018 ◽

Vol 96 (6) ◽

pp. 618-623 ◽

Cited By ~ 3

Author(s):

Ahmet Goktan Aksu ◽

Ozgur Gunduz ◽

Ahmet Ulugol

Keyword(s):

Receptor Antagonist ◽

Motor Coordination ◽

Antinociceptive Effect ◽

Antinociceptive Activity ◽

Tail Flick ◽

Hot Plate ◽

Rotarod Test ◽

Antinociceptive Effects ◽

Cb2 Agonist ◽

Cannabinoid Agonist

The antinociceptive effects of cannabinoids and opioids have been known for centuries. Serotonin and its receptors are also known to play important roles in nociception. However, the contribution of spinal 5-HT5A receptors in antinociceptive effects of cannabinoids and opioids has not been studied. We conducted this study to clarify spinal mechanisms of the actions of the antinociceptive effects of cannabinoids and opioids. Hot plate and tail flick tests were used to assess the antinociceptive activity in Balb/c mice. WIN 55,212-2, a nonselective CB1 and CB2 agonist, and morphine exerted significant antinociceptive effects at 1, 3, and 10 mg/kg doses administered intraperitoneally in both hot plate and tail flick tests. The selective 5-HT5A receptor antagonist SB-699551 (10 nmol/mouse) was administered intrathecally 10 min before the agonists. SB-699551 significantly reduced the antinociceptive effect of both WIN 55,212-2 and morphine. In the rotarod test, WIN 55,212-2 disrupted the motor coordination at a dose of 10 mg/kg, while morphine did not affect this function at any dose. Our findings show that spinal 5-HT5A receptors are involved in the antinociceptive effects of WIN 55,212-2 and morphine.

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Faculty Opinions recommendation of Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718024977.793489001 ◽

2013 ◽

Author(s):

Larry Mattheakis

Keyword(s):

Opioid Receptor ◽

Antinociceptive Activity ◽

Δ Opioid Receptor ◽

Biased Agonist

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In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180220125406 ◽

2018 ◽

Vol 21 (3) ◽

pp. 215-221

Author(s):

Haroon Khan ◽

Muhammad Zafar ◽

Helena Den-Haan ◽

Horacio Perez-Sanchez ◽

Mohammad Amjad Kamal

Keyword(s):

In Silico ◽

Docking Studies ◽

In Vivo Studies ◽

In Vitro Assays ◽

Chronic Obstructive ◽

Lipoxygenase Inhibitors ◽

Lipoxygenase Inhibition ◽

In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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Promising Anti-stroke Signature of Voglibose: Investigation through In- Silico Molecular Docking and Virtual Screening in In-Vivo Animal Studies

Current Gene Therapy ◽

10.2174/1566523220999200726225457 ◽

2020 ◽

Vol 20 (3) ◽

pp. 223-235

Author(s):

Pooja Shah ◽

Vishal Chavda ◽

Snehal Patel ◽

Shraddha Bhadada ◽

Ghulam Md. Ashraf

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

In Silico ◽

Reductase Activity ◽

Infarct Volume ◽

Docking Studies ◽

Serum Glucose ◽

In Vivo Studies ◽

In Silico Molecular Docking

Background: Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications. Objective: The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes. Material and Methods: In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity. Results: In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate. Conclusion: In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

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Aristolochia trilobata: Identification of the Anti-Inflammatory and Antinociceptive Effects

Biomedicines ◽

10.3390/biomedicines8050111 ◽

2020 ◽

Vol 8 (5) ◽

pp. 111

Author(s):

Dayana da Costa Salomé ◽

Natália de Morais Cordeiro ◽

Tayná Sequeira Valério ◽

Darlisson de Alexandria Santos ◽

Péricles Barreto Alves ◽

...

Keyword(s):

Enzyme Inhibitor ◽

Interleukin 1 ◽

Antinociceptive Effect ◽

Cholinergic Receptor ◽

Hot Plate ◽

Nitric Oxide Synthase Inhibitor ◽

Antinociceptive Effects ◽

Anti Inflammatory ◽

Skin Affection ◽

Synthase Inhibitor

Aristolochia trilobata, popularly known as “mil-homens,” is widely used for treatment of stomach aches, colic, asthma, pulmonary diseases, diabetes, and skin affection. We evaluated the antinociceptive and anti-inflammatory activities of the essential oil (EO) and the main constituent, 6-methyl-5-hepten-2-yl acetate (sulcatyl acetate, SA). EO and SA (1, 10, and 100 mg/kg, p.o.) were evaluated using chemical (formalin-induced licking) and thermal (hot-plate) models of nociception or inflammation (carrageenan-induced cell migration into the subcutaneous air pouch, SAP). The mechanism of antinociceptive activity was evaluated using opioid, cholinergic receptor antagonists (naloxone and atropine), or nitric oxide synthase inhibitor (L-NAME). EO and SA presented a central antinociceptive effect (the hot-plate model). In formalin-induced licking response, higher doses of EO and SA also reduced 1st and 2nd phases. None of the antagonists and enzyme inhibitor reversed antinociceptive effects. EO and SA reduced the leukocyte migration into the SAP, and the cytokines tumor necrosis factor and interleukin-1 (TNF-α and IL-1β, respectively) produced in the exudate. Our results are indicative that EO and SA present peripheral and central antinociceptive and anti-inflammatory effects.

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High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity

Nature Communications ◽

10.1038/s41467-021-23954-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhou Fang ◽

Junjian Chen ◽

Ye Zhu ◽

Guansong Hu ◽

Haoqian Xin ◽

...

Keyword(s):

Antimicrobial Activity ◽

High Throughput ◽

High Throughput Screening ◽

Rational Design ◽

Click Reaction ◽

Reaction Times ◽

Great Promise ◽

Biomaterial Surfaces

AbstractPeptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.

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