19,670 research outputs found
Design and synthesis of Heterocyclic Compounds as CB2 Selective Agoists
No full textCannabinoids are present in Indian hemp, Cannabis sativa L., and have been used since antiquity as medicinal agents(1). Interest in cannabinoid pharmacology has rapidly increased since the discovery of the endocannabinoid system (ECS), which includes cannabinoid receptors, the endocannabinoids (anandamide and 2-arachidonoylglycerol), metabolizing enzymes (fatty acid amide hydrolase and monoglyceride lipase), and aspecific cellular uptake system (the anandamide transporterprotein).
Cannabinoids exhibit a complex array of pharmacological effects that are generally considered to be mediated through at least two G-protein- coupled (GPCR) seven-transmembrane receptors. One of these receptors, designated CB1, is found principally in the central nervous system but it is also present in some peripheral organs. The CB2 receptor was originally identified from macrophages present in the spleen, and it is expressed primarily in the cells associated with the immune system, like spleen, thymus, and tonsils. The physiological and putative therapeutic potential of the CB2 receptor largely remains unexplored; however, recent data indicate that CB2 cannabinoid receptors participate in the control of peripheral pain, inflammation, osteoporosis, growth of malignant gliomas, tumors of immune origin, and immunological disorders such as multiple sclerosis. Furthermore, CB2 agents could be exploited for prevention of Alzheimer’s disease pathology, given of the presence of the CB2 receptor in the brain microglial cells,(2) and may be the basis for developing new drugs for the treatment of amyotrophic lateral sclerosis.(3) Because of the virtually exclusive peripheral expression of CB2, selective CB2 ligands should be devoid of the undesired central nervous system effects typical of (-)-trans-?9-tetrahydrocannabinol, the major psychoactive component of Cannabis sativa L.
In a previous work the binding results of a series of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives(4) was reported. Furthermore, recently the three-dimensional models of the CB1 and CB2 receptors by means of a molecular modeling producer was constructed, and a series of CB2 ligands were, docked into both receptors, showing that the CB2 model was reliable and predictive.(5)
In this work, basing on the docking results, , I designed and synthesized new 7-methyl-1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, analogues derivatives in which the methyl group was removed or substituted with a chlorine atom, fluorine atom, metoxy group and dimethylamino group and new quinolin-4(1H)-on-3-carboxamide derivatives.
The studies of automated docking have showed that all the 1,8-naphthyridine derivatives tested could form an intramolecular H bond between the carbonylic oxygen and the amidic NH, creating a pseudocycle planar with the naphthyridine ring, and our studies suggested that this interaction was quite strong.(5)
To verify the hypothesis of the formation of a planar pseudocycle interaction inside the CB, I synthesized to tested some new compounds characterized by:
• the presence of a hydroxy group in position 4 of the naphthyridine nucleus, instead of the carbonyl oxygen atom, and by partial removal of the aromaticity of the cycle.
• closing of the O in position 4 with the amidic NH in a cycle to five atoms, to mime the pseudocycle planar of the energetic form more stable.
• shifting from position 3 to position 2 of the heterocyclic nucleus, of the carboxamide group.
Successful I synthesized new 1,8-naphthrydine characterized by the presence of a carbonilic group in position 2, to verify if this shift could be create a new interaction of binding site receptor. New 1,8-naphthrydine and quinoline derivatives characterized by the presence of a carbonilic group in positions 4 and 2, and finally to verify the importance of the presence of both aromatic rings in the central lipophilic bicyclic core, I have synthesized the pyridin compounds.
(1) Dewick, P. M. Medicinal Natural Products. A Biosynthetic Approach, 2nd ed.; John Wiley & Sons: New York, 2002; pp 86-89.
(2) Stella, N. Cannabinoid signaling in glial cells. Glia 2004, 48, 267-277.
(3) Kim, K.; Moore, D.H.; Markriyannis, A.; Abood, M.E.. Eur J Pharmacol. 2006, 542,100.
(4) Ferrarini, P. L.; Calderone, V.; Cavallini, T.; Manera, C.; Saccomanni, G.; Pani, L.; Ruiu, S.; Gessa, G. L .. Bioorg. Med. Chem. 2004, 12, 1921-1933.
(5) Tuccinardi, T.; Ferrarini, P. L.; Manera, C.; Ortore, G.; Saccomanni, G.; Martinelli, A. . J. Med. Chem. 2006, 49, 984-994
Ultrastructural Assessment of Granulomas in the Liver of Perch (Perca fluviatilis) Infected by Tapeworm
No full textSummary Granulomas caused by migration of larvae of a helminth parasite, Triaenophorus nodulosus, within the liver of perch (Perca fluviatilis) from Rimov Dam Lake (Czech Republic) were assessed by transmission electron microscopy. Lesions were found in the liver of 29 out of 34 perch examined (85.2%) and there were between 1 and 15 T. nodulosus larvae identified per host. Pathological changes were more severe in livers containing more granulomas. Within the granulomas, there were three concentric regions: an outer layer of fibrous connective tissue, a middle clear epithelioid layer and a central dark spindle cell layer. The outer layer contained mast cells, fibroblasts, thick collagen bundles and epithelioid cells. The granulomas contained few lymphocytes and macrophages. Hepatocytes adjacent to the granulomas showed pronounced degeneration (ranging from vacuolar degeneration to acute cellular swelling)
Synthesis of 3- or 4-phenyl-1,8-naphthyridine derivatives and evaluation of antimycobacterial and antimicrobial activity
No full textA series of 3- or 4-phenyl-1,8-naphthyridine derivatives variously substituted in the positions 2, 6 and 7 were synthesized and evaluated for in vitro evaluation for their antimycobacterial activity as part of a TAACF TB screening program under the direction of the US National Institute of Health, NIAID division. Several compounds showed an interesting activity when tested at a concentration of 6.25 μg/ml against Mycobacterium tuberculosis H 37Rv and in particular compounds 2a, 4a,d, 8a,d and 8i, exhibit a % inhibition from 91 to 99. Among these, compounds 2a, 8a and 8d appeared to have a good activity with minimum inhibitory concentrations (MICs) of 6.25 μg/ml. On the basis of the biological results, the most effective substituent in position 2 or 7 seems to be the piperidinyl group. The introduction of a morpholinyl group either in position 2 or 7 of the heterocycle ring caused a decrease in activity. The 1,8-naphthyridine derivatives were also tested in vitro for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria
The use of fractal dimension and lacunarity in the characterization of mast cell degranulation in rainbow trout (Onchorhynchus mykiss)
No full textFractal analysis is a reliable method for describing, summarizing object complexity and heterogeneity and has been widely used in biology and medicine to deal with scale, size and shape management problems. The aim of present survey was to use fractal analysis as a complexity measure to characterize mast cells (MCs) degranulation in a rainbow trout ex vivo model (isolated organ bath). Compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine with formaldehyde, was adopted as MCs degranulation agent in trout intestinal strips. Fractal dimension (D), as a measure of complexity, ‘roughness’ and lacunarity (λ), as a measure of rotational and translational invariance, heterogeneity, in other words, of the texture, were compared in MCs images taken from intestinal strips before and after compound 48/80 addition to evaluate if and how they were affected by degranulation. Such measures were also adopted to evaluate their discrimination efficacy between compound 48/80 degranulated group and not degranulated group and the results were compared with previously reported data obtained with conventional texture analysis (image histogram, run-length matrix, co-occurrence matrix, autoregressive model, wavelet transform) on the same experimental material. Outlines, skeletons and original greyscale images were fractal analysed to evaluate possible significant differences in the measures values according to the analysed feature. In particular, and considering outline and skeleton as analysed features, fractal dimensions from compound 48/80 treated intestinal strips were significantly higher than the corresponding untreated ones (paired t and Wilcoxon test, p < 0.05), whereas corresponding lacunarity values were significantly lower (paired Wilcoxon test, p < 0.05) but only for outline as analysed feature. Outlines roughness increase is consistent with an increased granular mediators interface, favourable for their biological action; while lacunarity (image heterogeneity) reduction is consistent with the biological informative content decrease, due to granule content depletion. In spite of the significant differences in fractal dimension and lacunarity values registered according to the analysed feature (greyscale obtained values were, on average, lower than those obtained from outlines and skeletons; General Linear Model, p < 0.01), the discrimination power between not degranulated and degranulated MCs was, on average, the same and fully comparable with previously performed texture analysis on the same experimental material (outline and skeleton misclassification error, 20% [two false negative cases]; greyscale misclassification error, 30% [two false negative cases and one false positive case]). Fractal analysis proved to be a reliable and objective method for the characterization of MCs degranulation
Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors
No full textCannabinoid receptors have been studied extensively in view of their potential functional role in several physiological and pathological processes. For this reason, the search for new potent, selective ligands for subtype CB receptors, CB(1) and CB(2), is still of great importance, in order to investigate their role in various physiological functions. The present study describes the synthesis and the biological properties of a series of 1,8-naphthyridine derivatives, characterised by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or arylalkyl substituent in position 1. These compounds were assayed for binding both to the brain and to peripheral cannabinoid receptors (CB(1) and CB(2)). The results obtained indicate that the naphthyridine derivatives examined possess a greater affinity for the CB(2) receptor than for the CB(1) receptor. In particular, derivatives 6a and 7a possess an appreciable affinity for the CB(2) receptor, with K(i) values of 5.5 and 8.0 nM respectively; also compounds 4a, 5a and 8a exhibit a good CB(2) affinity, with K(i) values in the range of 10-44 nM. Furthermore, compounds 3g-i and 18 revealed a good CB(2) selectivity, with a CB(1)/CB(2) ratio >20
PCB concentrations in freshwater wild brown trouts (Salmo trutta trutta L) from Marche rivers, Central Italy
No full textThe purpose of this study is to evaluate the degree of PCBs contamination of wild brown trouts (Salmo trutta trutta L) caught in Marche Region rivers and to study the percentage contribution of the sum of the six indicators PCBs with respect to the sum of eighteen congeners in wild brown trouts. The determination of eighteen PCBs was made on the edible portion (fillets) of trouts by GC-ECD analysis. Fish samples were collected from fourteen rivers, selected to represent the fluvial pollution in the Marche Region. The total sum of eighteen congener concentrations was 8.2±0.9 ng/g wet weight. All the analysed samples showed a high variability of their congener profile even though the six PCBs indicators stood for 49.8% of the total PCBs. In the muscle of brown trout the Σ eighteen PCB and the Σ six PCB concentrations were not statistically correlated with the length and the body mass of specimens. Total PCB (Σ eighteen PCBs and Σ six PCBs) concentrations measured in the different sampling sites showed significant statistical differences among districts and, in the same district, among rivers (p<0.01). In particular, the lowest PCB levels (p<0.01) were detected in fish caught in Pesaro-Urbino Province rivers with the mean total PCB concentrations of 102.4±6.3 ng/g fat weight while the highest PCB levels were measured in specimens coming from Macerata Province rivers (1147.8±456.6 ng/g fat weight)
Implementation of a Broadband Photonics-assisted RF Amplifier Toward 5G Networks
No full textWe report the implementation of a photonics-assisted RF amplifier for broadband and multiband 5G networks. A 2 Gsymb/s signal with different digital modulation formats at 20 GHz and a 100 Msymb/s high-order digital modulated signal at 6 GHz have been used for characterizing the proposed technology as a function of the RF gain, signal-to-noise ratio and error vector magnitude. Experimental results demonstrate RF amplification, reconfigurability, distortion absence and low phase noise levels through 6, 20 and 38 GHz frequency bands, which have been considered potential for the future 5G networks
Grayscale differential box counting as a measure of complexity of liver texture in common carp (Cyprinus carpio) sub-chronically exposed to perfluorooctanoic acid (PFOA)
No full textPerfluorooctanoic acid (PFOA), a perfluorinated alkylated substance (PFAS), poses a worldwide concern for its wide distribution, bioaccumulation in food webs, long half-life in organisms, and potential toxic, carcinogenic and endocrine disrupting effects on animals. Fish are excellent candidates in aquatic biomonitoring programs and toxicologic testing, frequently focusing on liver due to its pivotal role in the health of the whole organism and its highly sensitivity to contaminants. Histopathology can be useful in evaluating toxicological effects on fish health and texture analysis can represent an objective, replicable diagnostic tool, potentially free from operator-dependent bias. In the present survey, liver histological texture was comparatively assessed in specimens of common carp (Cyprinus carpio) sub-chronically exposed to PFOA. Twenty specimens were exposed to two PFOA dosages (10 exposed to 200 ng l-1, 10 exposed to 2 mg l-1) for 56 days and compared to other 10 unexposed fish. Grayscale differential box counting (fractal dimension and lacunarity) was evaluated on representative pictures taken from liver histological sections. Differential box counting was implemented by converting two-dimensional grayscale images into pseudo three-dimensional information. Hence, fractal dimension and lacunarity acted as a measure of the complexity and of the heterogeneity of the grayscale levels distribution, respectively. Redundancy Analysis (RDA) was performed on the obtained numerical data in order to summarize the part of grayscale differential box counting variation that is explained by the following biometric/experimental variables: PFOA liver concentration, liver mass, proliferating cell nuclear antigen (PCNA) positive nuclei, after removing the effects of fish total length. The t-values of the regression coefficients of liver PFOA concentration and of liver mass with both fractal dimension and lacunarity, and of PCNA positive nuclei with lacunarity, showed values larger than 2, while the t-value of the regression of PCNA positive nuclei with fractal dimension appeared to be close to 2. Considering the selected biometric/experimental variables, liver PFOA concentration correlated with PCNA positive nuclei but did not correlate with liver mass, whereas PCNA positive nuclei correlated with liver mass. Interestingly, fractal dimension contributed better than lacunarity in treatment groups ordination. Recently, fractal analysis has been adopted to estimate the complexity loss associated with pathological changes. In the present survey, contrary as expected, liver texture modification related to liver PFOA concentration increase was associated with a significant complexity increase, related to reversible changes (hydropic degeneration), possibly acting as an initially adaptive strategy, rather than representing mere degeneration, to cope with PFOA challenge. The possible occurrence of a hormetic response should be further investigated
Pharmacokinetics of Tramadol and its Metabolites M1, M2 and M5 in Horses Following Intravenous, Immediate Release (Fasted/Fed) and Sustained Release Single Dose Administration
No full textTramadol (T) is a centrally acting analgesic structurally
related to codeine and morphine. This drug displays
a weak affinity for the m and d-opioid receptors, and
weaker affinity for the k-subtype; it also interferes with
the neuronal release and reuptake of serotonin and noradrenaline
in the descending inhibitory pathways. The
metabolism of this drug has been investigated in different
animals (rats, mice, Syrian hamsters, guinea pigs,
rabbits, and dogs) and humans; similar metabolites
are produced but in different amounts. The major
metabolic pathways involved in phase I metabolite production
(M1M5) are O-demethylation, N-demethylation,
and N,N-demethylation. The aim of the
current study is to evaluate the pharmacokinetic profile
of T in the horse, and its M1, M2, and M5 metabolites
after single-dose administration (5 mg/kg body weight
[BW]) by intravenous, sustained-release tablets and immediate-
release capsules. We also will investigate the potential
effects of fasting and feeding on bioavailability of
immediate-release capsules. The study design was divided
into four randomized phases. Twenty-four gelding
Italian trotter race horses were divided into four
groups (6 animals each) and administered T intravenously,
with T immediate-release capsules in a fasting
status, T immediate-release capsules in a feeding status,
and T sustained-release in fasting status. Blood samples
were collected at different times and analyzed by highpressure
liquid chromatography (HPLC) with fluorimetric
detection. The limit of quantification was 5
ng/ml for T, M1, and M2, and 10 ng/ml for M5. A
one-compartment model best fit the plasma concentrations
of T and M2 after all treatments. Unfortunately,
for M1 and M5, it was not always possible to fit plasma
curves because of very low and variable concentrations.
M2 was the main metabolite produced in the four different
treatments and its concentration was higher than the
concentration of T after sustained-release administration.
Conversely, M1, the main metabolite in humans,
and M5 seemed to be only marginally produced in the
horse. When T was administered in both fasted and
fed states, variations in some pharmacokinetic parameters
were not considered clinically significant. We concluded
that T could be administered in either a fasted
or a fed condition
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