Discovery of orexant and anorexant agents with indazole scaffold endowed with peripheral antiedema activity

CB1 receptors and endocannabinoids are integrated components of neuronal networks controlling different organism’s functions, such as appetite and food intake in the hypothalamus. A series of Rimonabant/Fubinaca hybrids have been synthesized in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied in cannabinoid receptor binding assay and functional receptor assay in vitro, the most active among them as agonist (LONI 11) and antagonist (LONI 4) were tested in vivo to evaluate their ability to stimulate or suppress the feeding behavior after i.p. administration. For LONI 11 formalin test and tail flick tests after s.c. and i.c.v. routes respectively, were also performed in vivo with the aim to investigate the antinociceptive effect at the central or peripheral level. In the Zymosan-induced edema and hyperalgesia, LONI 11 reduced the % paw volume increase and % paw latency after s.c. administration, also suggesting a potential anti-inflammatory activity at the periphery. Keywords. Cannabinoid receptor, Rimonabant, food intake, anorexant agent, edema

An overview on plants cannabinoids endorsed with cardiovascular effects.

Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life. The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis. Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics. One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs. The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system

Chemical composition and biological activity of Capparis spinosa L. from Lipari Island

Several plants belonging to the genus Capparis are the focus of growing interest due to their singular nutritional and medicinal properties. In the present study, flower bud samples from C. spinosa L. (Lipari Island, Italy) were subjected to decoction, Soxhlet, and microwave extraction techniques and the individual extracts investigated to better characterize the phytochemical and antioxidant profiles of the plant. Total phenolic and flavonoid amounts, phenolic composition, radical scavenging as well as reductive and metal chelating properties were determinated by well-established chemical and analytical procedures. Furthermore, cholinesterase inhibitory effects were evaluated by Ellman's method. Fatty acid percentage and essential oil composition were also detected by GC and GC-MS techniques respectively. Rutin was found to be the major component in the studied extracts. The Soxhlet extract exhibited the strongest radical scavenging and reductive activities as compared to the other extracts, most probably due to the highest concentration of phenolics, especially rutin. The best cholinesterase inhibitory effect was observed in the microwave extract. Palmitic acid was the most abundant fatty acid in the studied oil, whereas docosane was the major volatile compound in the essential oil. Present data corroborate the multipurpose potential of C. spinosa for designing bio-based drug formulations or functional applications. (c) 2018 SAAB. Published by Elsevier B.V. All rights reserved

Discovery of Novel mu-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Morphine, oxycodone, fentanyl, and other mu-opioid receptors (MOR) agonists have been used for decades in antinociceptive therapies. However, these drugs are associated with numerous side effects, such as euphoria, addiction, respiratory depression, and adverse gastrointestinal reactions, thus, circumventing these drawbacks is of extensive importance. With the aim of identifying novel peptide ligands endowed with MOR inhibitory activity, we developed a virtual screening protocol, including receptor-based pharmacophore screening, docking studies, and molecular dynamics simulations, which was used to filter an in-house built virtual library of tetrapeptide ligands. The three top-scored compounds were synthesized and subjected to biological evaluation, revealing the identity of a hit compound (peptide 1) endowed with appreciable MOR inverse agonist effect and selectivity over delta-opioid receptors. These results confirmed the reliability of our computational approach and provided a promising starting point for the development of new potent MOR modulators

On resin click-chemistry-mediated synthesis of novel enkephalin analogues with potent anti-nociceptive activity

Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the μ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.University of ArizonaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists.

Kynurenine (kyn) and kynurenic acid (kyna) are well-defined metabolites of tryptophan catabolism collectively known as "kynurenines", which exert regulatory functions in host-microbiome signaling, immune cell response, and neuronal excitability. Kynurenine containing peptides endowed with opioid receptor activity have been isolated from natural organisms; thus, in this work, novel opioid peptide analogs incorporating L-kynurenine (L-kyn) and kynurenic acid (kyna) in place of native amino acids have been designed and synthesized with the aim to investigate the biological effect of these modifications. The kyna-containing peptide (KA1) binds selectively the m-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio m/d/k = 1:514:10000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for m, d, and k-opioid receptors, with efficacy and potency (Emax = 209.7 + 3.4%; LogEC50 = -5.984 + 0.054) higher than those of the reference compound DAMGO. This novel oligopeptide exhibits a strong antinociceptive effect after i.c.v. and s.c. administrations in in vivo tests, according to good stability in human plasma (t1/2 = 47 min)

Discovery of Kynurenines containing oligopeptides as potent opioid receptor agonists

Kynurenine (kyn) and kynurenic acid (kyna) are well-defined metabolites of tryptophan catabolism collectively known as “kynurenines”, which exert regulatory functions in host-microbiome signaling, immune cell response, and neuronal excitability. Kynurenine containing peptides endowed with opioid receptor activity have been isolated from natural organisms; thus, in this work, novel opioid peptide analogs incorporating L-kynurenine (L-kyn) and kynurenic acid (kyna) in place of native amino acids have been designed and synthesized with the aim to investigate the biological effect of these modifications. The kyna-containing peptide (KA1) binds selectively the μ-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio μ/δ/κ = 1:514:10,000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for μ, δ, and κ-opioid receptors, with efficacy and potency (Emax = 209.7 + 3.4%; LogEC50 = −5.984 + 0.054) higher than those of the reference compound DAMGO. This novel oligopeptide exhibits a strong antinociceptive effect after i.c.v. and s.c. administrations in in vivo tests, according to good stability in human plasma (t1/2 = 47 min)

Chemical characterization, antioxidant properties and enzyme inhibition of Rutabaga root's pulp and peel (Brassica napus L.)

Abstract Rutabaga (Brassica napus L.) belonging to Brassicaceae family, is a rich source of polyphenols and glucosinolates. Its consumption in human diet is highly appreciated for its nutritional contribution and health benefits. Brassica napus L. is recognized as the world's most widely grown temperate oilseed crop containing erucic acid for industrial applications, plants germination, animal feed and fuel. In this work we prepared two different extracts of Rutabaga root's pulp and peel, e.g. ultrasound assisted extract (UAE) and homogenizer assisted extract (HAE). The four extracts have been analyzed by HPLC-MS to assess the phytochemical characterization and tested by antioxidant and enzyme inhibitor assays. Rutabaga pulp and peel extracts possess tyrosinase and glucosidase inhibitory activities together with a moderate antioxidant ability. Our results show a high level of glucosinolates, in particular neoglucobrassicin in the peel extract, which let us suppose a potential application as crop in industry and as supplement in human diet

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