Development of novel oxazolo[5,4- d ]pyrimidines as competitive CB 2 neutral antagonists based on scaffold hopping

A series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB1/CB2 cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB2 ligands with Ki values less than 1 μM. It is noteworthy that 2-(2-chlorophenyl)-5-methyl-7-(4-methylpiperazin-1-yl) oxazolo[5,4-d]pyrimidine 47 and 2-(2-chlorophenyl)-7-(4-ethylpiperazin-1-yl)- 5-methyloxazolo[5,4-d]pyrimidine 48 showed CB2 binding affinity in the nanomolar range and significant selectivity over CB1 receptors. Interestingly, functionality studies imply that they behave as competitive neutral antagonists. Moreover, all tested compounds are devoid of cytotoxicity toward several cell lines, including Chinese hamster ovary cells (CHO) and human colorectal adenocarcinoma cells HT29

Neuromuscular Consequences of an Extreme Mountain Ultra-Marathon

We investigated the physiological consequences of one of the most extreme exercises realized by humans in race conditions: a 166-km mountain ultra-marathon (MUM) with 9500 m of positive and negative elevation change. For this purpose, (i) the fatigue induced by the MUM and (ii) the recovery processes over two weeks were assessed. Evaluation of neuromuscular function (NMF) and blood markers of muscle damage and inflammation were performed before and immediately following (n = 22), and 2, 5, 9 and 16 days after the MUM (n = 11) in experienced ultra-marathon runners. Large maximal voluntary contraction decreases occurred after MUM (−35% [95% CI: −28 to −42%] and −39% [95% CI: −32 to −46%] for KE and PF, respectively), with alteration of maximal voluntary activation, mainly for KE (−19% [95% CI: −7 to −32%]). Significant modifications in markers of muscle damage and inflammation were observed after the MUM as suggested by the large changes in creatine kinase (from 144±94 to 13,633±12,626 UI L−1), myoglobin (from 32±22 to 1,432±1,209 µg L−1), and C-Reactive Protein (from <2.0 to 37.7±26.5 mg L−1). Moderate to large reductions in maximal compound muscle action potential amplitude, high-frequency doublet force, and low frequency fatigue (index of excitation-contraction coupling alteration) were also observed for both muscle groups. Sixteen days after MUM, NMF had returned to initial values, with most of the recovery process occurring within 9 days of the race. These findings suggest that the large alterations in NMF after an ultra-marathon race are multi-factorial, including failure of excitation-contraction coupling, which has never been described after prolonged running. It is also concluded that as early as two weeks after such an extreme running exercise, maximal force capacities have returned to baseline

Synthesis of bioorganometallic nanomolar-potent CB2agonists containing a ferrocene unit

A small library of ferrocene-containing amides has been synthesized using standard amide coupling chemistry with ferrocenylamine. Ferrocene analogues of known bioactive adamantylamides were shown to be effective cannabinoid receptor (CB1 and CB2) agonists, displaying, in many cases, single-digit nanomolar potency. Three final ferrocene-containing derivatives have been characterized in the solid state by X-ray crystallography and display intramolecular hydrogen bonding of the type NH---C═O. N-Methylation of the amide, confirmed by X-ray crystallography, leads to both loss of hydrogen bonding and biological activity

La mosaïque de l'alternance

International audienceDepuis de nombreuses années, et avec une certaine constance, l’alternance et l’apprentissage sont positionnés comme des leviers pour lutter contre le chômage des jeunes – dans la lutte contre le décrochage scolaire et pour une meilleure insertion professionnelle des jeunes. Le monde de l’entreprise pousse en particulier au développement de ces cursus et ce, dans une perspective d’employabilité ; le rapport interministériel publié en mars 2014 va lui aussi dans ce sens. Ce numéro de Diversité propose ainsi de rappeler les cadres précis de l’alternance et de l’apprentissage et de mieux en connaître les publics, les limites et les enjeux, bien au-delà de la seule question de l’employabilité

L'alternance, une voie pour un nouveau dialogue éducatif ?

National audienc

Développement de nouveaux ligands sélectifs des récepteurs CB2 et de nouveaux inhibiteurs de la FAAH dans le traitement des maladies inflammatoires chroniques de l'intestin

Des études récentes ont montré que l'anandamide, le principal ligand endogène des récepteurs aux cannabinoïdes CB1 et CB2, possède des effets analgésiques, antidépresseurs et anti-inflammatoires. Dans la perspective de traitement des maladies inflammatoires chroniques de l'intestin (MICI), notre approche a été de développer de nouveaux ligands sélectifs du récepteur CB2 permettant de moduler l inflammation sans provoquer d effets secondaires centraux, et de nouveaux inhibiteurs de la principale enzyme du métabolisme de l anandamide, la fatty acid amide hydrolase (FAAH). Ainsi, sur la base des travaux antérieurs de notre groupe, une nouvelle série d agonistes sélectifs du récepteur CB2 et deux nouvelles séries d'inhibiteurs de FAAH s articulant autour de plusieurs hétérocycles différents ont été conçues, synthétisées et évaluées pour leur activité biologique. Les résultats pharmacologiques ont révélé des affinités sélectives pour le récepteur CB2 et des activités inhibitrices de la FAAH pour certains composés. Ces travaux ont permis d'établir des relations structure-activité essentielles pour la conception d agoniste CB2 mais aussi pour la conception de composés prometteurs à double activités: agonistes CB2 / inhibiteurs FAAH. Enfin, deux composés agonistes sélectifs CB2 ont été évalués pour leurs propriétés anti-inflammatoires au niveau intestinal sur modèle murin de colite induite au DSS.Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new CB2-selective ligands which are able to modulate inflammation without triggering psychotropic effects, and new inhibitors of the main anandamide-degradation enzyme, the fatty acid amide hydrolase (FAAH). Therefore, based on previous works in our group, a new series of CB2-selective agonists and two new series of FAAH inhibitors based on different scaffolds was designed, synthesized and evaluated for their biological activity. The pharmacological results showed CB2-selective agonist activities and FAAH-inhibitory activities for some compounds. This work helped to establish essential structure-activity relationships for the design of CB2-selective agonist but also for the design of promising multitarget compounds: CB2 agonists / FAAH inhibitors. Finally, two CB2-selective agonist compounds were evaluated for their anti-inflammatory properties on DSS-induced colitis mouse model.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Du cannabis aux agonistes sélectifs du récepteur CB

Utilisée à l’origine en Asie pour traiter douleurs, spasmes, nausées et insomnies, la marijuana est le psychotrope le plus consommé au monde. L’intérêt du cannabis médical a été reconsidéré depuis peu, menant à de nombreuses recherches et à la commercialisation de médicaments. Les cannabinoïdes naturels et synthétiques exercent des effets bénéfiques dans de nombreuses maladies. Ils sont toutefois accompagnés d’effets indésirables psychiatriques et cognitifs présumés liés au récepteur CB1. Les recherches actuelles tendent à concevoir des molécules thérapeutiques agonistes CB2 sans effets secondaires centraux psychotropes

Reconsidering the origins of isotopic variations in Ocean Island Basalts: Insights from fine-scale study of São Jorge Island, Azores archipelago

New major and trace element and Sr–Nd–Pb isotope data have been determined for 21 basaltic samples from São Jorge Island, Azores archipelago. Samples can be separated into two groups best identified in a plot of 208Pb/204Pb versus 206Pb/204Pb where they form two sub-parallel mixing arrays. Lavas from the old (Topo) formation have lower 208Pb/204Pb for a given 206Pb/204Pb and more radiogenic Sr than samples from intermediate (Rosais) and young (Manadas) formations. Topo samples also tend to have higher MgO contents and lower incompatible trace element concentrations. Both Pb mixing arrays can be related to mixing of plume melts having a HIMU-like Pb isotope signature with two depleted components. One depleted component is best seen in analyses of Topo samples and is interpreted to represent upper mantle material from the nearby Mid-Atlantic ridge. The second depleted component has Sr–Nd–Pb isotopic characteristics similar to E-MORB and resides in the oceanic crust basement under São Jorge. Pb isotope analyses of lavas from São Jorge make it possible to re-define the Terceira end-member of the Azores archipelago, moving its composition to more radiogenic Pb with 206Pb/204Pb ~ 20.51, 207Pb/204Pb ~ 15.67 and 208Pb/204Pb ~ 39.56, at 143Nd/144Nd ~ 0.51295 and 87Sr/86Sr ~ 0.70375. Extending the interpretations made for the origins of the São Jorge isotopic mixing arrays to other islands from the Azores archipelago (Pico, Faial, Terceira and São Miguel), we show that most of the isotopic variability recorded by Azores magmas can be related to mixing of plume melts with two distinct and homogeneous signatures as well as several other components dispersed in the shallow mantle/lithosphere under the Azores. This illustrates how caution is required when interpreting ocean island basalt isotopic data as reflecting their deep mantle plume source, and subsequently for constraining mantle topology

Mantle plume heterogeneity versus shallow-level interactions: A case study, the São Nicolau Island, Cape Verde archipelago

We present new Sr–Nd–Pb isotopic data, as well as major- and trace-element concentrations, for 19 basaltic samples from São Nicolau Island, Cape Verde archipelago. Fine-scale study of the island argues in favor of mixing between four endmembers to explain isotopic variations of collected samples: 1) a radiogenic endmember (87Sr/86Sr ~ 0.7034; 143Nd/144Nd ~ 0.51285; 206Pb/204Pb ~ 20.0; 207Pb/204Pb ~ 15.65; 208Pb/204Pb ~ 39.8) representative of the Cape Verde plume deep source; 2) an unradiogenic endmember having isotopic compositions resembling those of Atlantic MORB dredged at the same latitude; 3) a low Sr–high Nd and Pb endmember identified as the Jurassic MORB basement of the archipelago; and 4) São Vicente-like Cape Verde carbonatites. Compositional and isotopic results show that most of the measured variations can be related to mixing of plume-derived melts with shallow-level reservoirs. Therefore the source heterogeneity of the Cape Verde plume is much smaller than the one sampled in basaltic samples. This observation illustrates how caution is required when interpreting global OIB data in terms of mantle topology without filtering from the contribution of shallow-level reservoirs

Relations entre la consommation d'oxygène et des mesures accélérométriques en course à pied sur piste

Communication brève : analyse des relations entre la consommation d'oxygène et des mesures accélérométriques triaxiales (Locometrix à 100 Hz) réalisées en zone lombaire médiane lors d'exercices de course à pied sur piste