Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Design, synthesis and biological profile of mixed opioid agonist/N-VGCC blocker peptides

In this paper we reported the synthesis and the in vitro and the in vivo biological evaluation of linear pseudo-peptides incorporating the N-VGCC blocker tripeptide Phe-NMe-Leu-Tyr(OBz)-NtBu and the biphalin pharmacophore Tyr-D-Ala-Gly-Phe. The novel sequences have been designed by using amino acids of different length to join the two pharmacophores and explore the structure-activity relationships of the novel compounds

Synthesis and Investigation of Anti-Bacterial Effects of 2-amino-5-Nitrothiophene Derivatives

Introduction: The increasing drug resistance of bacteria against different antibiotics is a cause of development of antimicrobial compounds. The aim of this study was to investigate the synthesis and evaluation of antibacterial effects of 2-amino-5-nitrothiophene derivatives against Staphylococcus aureus and Escherichia coli. Strains.   Materials & Methods: As the first stage, 2-amino-5-nitro-thiophene derivatives were synthesized. The structures of the synthesized compounds were confirmed by means of IR, 1H NMR and 13C NMR measurements. In the second phase, these compounds were evaluated for antimicrobial effects by Agar Well Diffusion Method against Staphylococcus aureus and Escherichia coli. Strains. Then, the minimum inhibitory concentration (MIC) of these compounds were evaluated.   Findings: According to our finds, reaction of malononitrile, aryl isothiocyanate and bromonitromethane in the presence of sodium ethoxide in ethanol led to preparation of compounds 4a-e. The antibacterial effects showed that all the compounds had inhibitory effects against Staphylococcus aureus.   Discussion & Conclusion: Our investigation concluded that the structure-activity relationship (SAR) results indicated that the compound 4a showed a potent antibacterial activity against Staphylococcus aureus, while this combination proved no effects on Escherichia coli. 4c and 4d compounds demonstrated an inhibitory effect on Escherichia coli strain, while the compounds 4b and 4e indicated similar effects on both the bacteria (Staphylococcus aureus and Escherichia coli). Meanwhile, efficacy of the compounds4b and 4e against Staphylococcus aureus and Escherichia coli was the same. &nbsp

Glycyrrhetinic Acid Inhibits Cell Growth and Induces Apoptosis in Ovarian Cancer A2780 Cells

Purpose: Accumulating evidence indicates that glycyrrhizin (GZ) and its hydrolyzed metabolite 18-β glycyrrhetinic acid (GA) exhibit anti-inflammatory and anticancer activities. The objective of this study was to examine the in vitro cytotoxic activity of GA on human ovarian cancer A2780 cells. Methods: A2780 cells were cultured in RPMI1640 containing 10% fetal bovine serum. Cells were treated with different doses of GA and cell viability and proliferation were detected by dye exclusion and 3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays. Apoptosis induction and expression of Fas and Fas ligand (FasL) were analyzed by flow cytometry. Results: We observed that GA decreases cell viability and suppressed cells proliferation in a dose-dependent manner as detected by dye-exclusion and XTT assayes. In addition, our flow cytometry data show that GA not only induces apoptosis in A2780 cells but also upregulates both Fas and FasL on these cells in a dose-dependent manner. Conclusion: we demonstrate that GA causes cell death in A2780 cells by inducing apoptosis

In Silico Identification of Tripeptides as Lead Compounds for the Design of KOR Ligands

The kappa opioid receptor (KOR) represents an attractive target for the development of drugs as potential antidepressants, anxiolytics and analgesics. A robust computational approach may guarantee a reduction in costs in the initial stages of drug discovery, novelty and accurate results. In this work, a virtual screening workflow of a library consisting of ~6 million molecules was set up, with the aim to find potential lead compounds that could manifest activity on the KOR. This in silico study provides a significant contribution in the identification of compounds capable of interacting with a specific molecular target. The main computational techniques adopted in this experimental work include: (i) virtual screening; (ii) drug design and leads optimization; (iii) molecular dynamics. The best hits are tripeptides prepared via solution phase peptide synthesis. These were tested in vivo, revealing a good antinociceptive effect after subcutaneous administration. However, further work is due to delineate their full pharmacological profile, in order to verify the features predicted by the in silico outcomes

Exploring the biological consequences of conformational changes in aspartame models containing constrained analogues of phenylalanine

<p>The dipeptide aspartame (Asp-Phe-OMe) is a sweetener widely used in replacement of sucrose by food industry. 2′,6′-Dimethyltyrosine (DMT) and 2′,6′-dimethylphenylalanine (DMP) are two synthetic phenylalanine-constrained analogues, with a limited freedom in χ-space due to the presence of methyl groups in position 2′,6′ of the aromatic ring. These residues have shown to increase the activity of opioid peptides, such as endomorphins improving the binding to the opioid receptors. In this work, DMT and DMP have been synthesized following a diketopiperazine-mediated route and the corresponding aspartame derivatives (Asp-DMT-OMe and Asp-DMP-OMe) have been evaluated <i>in vivo</i> and <i>in silico</i> for their activity as synthetic sweeteners.</p

Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge

d-Pen²,d-Pen⁵ enkephalin (DPDPE) is one of the most selective synthetic peptide agonists targeting the δ-opioid receptor. Three cyclic analogues of DPDPE containing a xylene bridge in place of disulfide bond have been synthesized and fully characterized as opioid receptors agonists. The <i>in vitro</i> activity was investigated showing a good affinity of <b>7a</b>–<b>c</b> for μ- and δ-receptors. <i>In vivo</i> biological assays revealed that <b>7b</b> is the most potent analogue with the ability to maintain high level of analgesia from 15 to 60 min following intracerebroventricular (i.c.v.) administration, whereas DPDPE was slightly active until 45 min. Compound <b>7b</b> induced long lasting analgesia also after subcutaneous administration, whereas DPDPE was inactive