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Les cannabinoïdes sont des composés provenant de la plante Cannabis sativa et possédant, entre autres,une activité analgésique. Ces composés exercent leurs effets via des récepteurs aux cannabinoïdes appelés CBR. Il existe deux types de CBR actuellement reconnus : CBl et CB2. CBl est principalement situé au niveau du système nerveux central (SNC).Il se trouve du côté présynaptique, où il exerce un effet inhibiteur de la neurotransmission. Ceci permet entre autres de moduler négativement les signaux douloureux.Outre les composés de Cannabis sativa, il existe des endocannabinoïdes, qui jouent également un rôle inhibiteur y compris dans le contrôle des signaux douloureux.Les CBR appartiennent à la super famille des récepteurs couplés aux protéines G (RCPG) . Après activation par un agoniste, CBl recrute et active la protéine G de type a i/o.Cette protéine G a pour effet d'inhiber l'adénylatecyclase et l'accumulation d'adénosine monophosphate cyclique (AMPc) dans la cellule. CBl active également des mitogen activated protein kinases (MAP kinases) ; les extracellular-signal regulated kinases de type 1 et 2 (ERK 1/2), via phosphorylation de celles-ci. Enfin, CBl a un effet sur des canaux membranaires tels que des canaux calciques ou potassiques. Ces voies de régulation sont terminées par l'activité GTPase de la sous unité a.Les protéines regulators of G protein signaling (RGS) sont des protéines à activité GAP(GTPase activating protein), qui stimulent la fonction GTPase intrinsèque à la protéine G. Ainsi, les RGS peuvent entrainer une terminaison plus rapide de la signalisation d'un RCPG. Des études précédentes ont montré que la protéine RGS4 présente une activité GP sur CBl. Ainsi, RGS4 pourrait provoquer un arrêt rapide de l'effet analgésique des endocannabinoïdes.Le but de ce travail a été d'étudier l'influence que RGS4 peut avoir sur les différentes composantes de la signalisation de CBl. Nous avons principalement étudié l'activation de la protéine G et celle d'ERK 1/2.Pour cela, nous avons utilisé un modèle cellulaire permettant l'expression simultanée de RGS4 et de CBl : les HEK Flp-ln T-Rex RGS4 (human embryonic kidney ; cellules rénales embryonnaires humaines), exprimant RGS4 de manière stable et inductible, que nous avons transfectées de manière transitoire avec un plasmide contenant la séquence codant pour CBl.Bien que nous n'ayons pas reussi à mettre en évidence une influence de RGS4 sur l'activation CBl-dependente des protéines G au moyen de test de GTPyS, nous avons démontré un effet inhibiteur de RGS4 sur l'activation d'ERKl/2 par CBl. Cet effet semble dépendre de l'agoniste utilisé. Ceci confirme l'influence de RGS4 sur au moins une partie de la signalisation de CBl. Considérant les résultats supplémentaires obtenus dans le laboratoire montrant : 1) une diminution de signalisation CBl dans les douleurs neuropathiques et 2) un effet analgésique des inhibiteurs des RGS4, ce travail suggère l'implication d'interaction entre CBl et RGS4 dans le développement de ce type de douleur. CBl is a G protein coupled receptor (GPCR), and is the target of cannabinoids compounds, such as THC,or endocannabinoids anandamide and 2-arachydonoylglycerol (2-AG). One of its roles in the central nervous system is to negatively modulate the transmission of pain signals. The RGS4 protein is a GTPase activating protein (GAP),which role is to facilitate the termination of GPCR's signaling by stimulating the intrinsic GTPase function of Ga, thus inactivating the G protein. Some studies have shown that RGS4 is able to interact with CBl, as GAP.ln this work, we wondered which parts of CBl signalling were influenced by RGS4. We studied the activation of the G protein, and the activation of ERKl/2. We used two different synthetic agonists (HU210 and CP55940) and one inverse agonist (SR141716A) of CBl,and we wondered if the effets of RGS4 were ligand dependant .Our results seem to indicate that RGS4 does not influence the activation of the G protein, but does have an effect on the activation of ERKl/2.The phosphorylation rate of ERKl/2 is indicative of its activation. Using HU210 and CP55940, we observed an elevation of the phosphorylation rate of ERKl/2, but this rate seems lower when RGS4 is overexpressed in the cells.Furthermore, our data suggest that HU210 and CP55940 do not induce the same effects on the activation of ERKl/2 in the presence of RGS4.SR141716A does not seem to have an effect on the phosphorylation rate of ERKl/2,but the presence of RGS4 enabled its inverse agonsist effects: the phosphorylation rate of ERKl/2 was lowered. These results tend to confirm that RGS4 has an influence on CBl signalling,and might be considered as a target in the treatment of some chronic pain.

Receptor, Cannabinoid, CB1 --- RGS4 protein --- Cannabis

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Since more than ten years, the WHO recognizes the obesity like a disease which must be treated. Physical exercises and diet are not any more sufficient to lose weight. Fortunately, the endocannabinoid system has been discovered and seems to have an important role in appetite and weight gain. Indeed, the cannabinoids are well known to increase appetite, and we noticed that the endocannabinoid system of obese persons is overactivated. The activation of CB1 receptors, presents in brain, adipose tissue, liver and skeletal muscles seems to be initially of hunger sensation and fat accumulation. Rimonabant, an antagonist and inverse agonist of CB1 receptor, is the first drug of this novel pharmaco-therapeutic class to be developed and studied in obesity. It has also a potential in tobacco and alcohol dependence, liver fibrosis, neuro-degenerative diseases and in schizophrenia; but we lack of data to confirm it. Clinical trials on Rimonabant have shown a weight loss of 5 to 10 % and a reduction of waist circumference until 10 cm. It also significatively improves lipid profile by decreasing the rate of triglycerides and increasing the rate of HDL-C. It ameliorates regulation of glycemia by increasing the insulin sensitivity. It also increases the rate of adiponectin and decreases levels of inflammatory markers. All these modifications are able to reduce cardiovascular diseases and diabetes risks which are complications of obesity and metabolic syndrome. The Rimonabant (Acomplia®) has been authorized to market in Europe in June 2006. However a lot of secondary psychiatric effects (depressions with suicide feelings) have been reported for its commercialization. The gain/risk ratio has been deemed unfavorable and lead to the withdrawal of market authorization in January 2009 Depuis plus d’une dizaine d’années, l’obésité est reconnue par l’OMS comme une maladie, qui nécessite une prise en charge. L’exercice physique et le régime alimentaire ne suffisent plus pour maigrir. Heureusement, le système endocannabinoïde a été découvert, et semble jouer un rôle important dans l’appétit et la prise de poids. En effet, la prise de cannabinoides est connue pour augmenter l’appétit, et on a remarqué un système endocannabinoïde hyperactif chez des patients obèses. L’activation des récepteurs CB1, présents aussi bien au niveau du cerveau que des tissus adipeux, du foie et des muscles serait à l’origine de la sensation de faim, et l’accumulation de graisse. Le Rimonabant, un antagoniste et agoniste inverse des récepteurs CB1 est le premier médicament de cette nouvelle classe thérapeutique à être développé et étudié dans le traitement de l’obésité. Il a également un potentiel dans les dépendances (au tabac, à l’alcool,…), la fibrose hépatique, les pathologies neurodégénératives et la schizophrénie, mais les études manquent pour le confirmer. Lors des essais cliniques, le Rimonabant a montré une réduction de 5 à 10 % du poids corporel et une diminution du tour de taille (pouvant aller jusqu’à 10 cm). Il améliore également de manière significative le profil lipidique en diminuant le taux de TG et en augmentant l’HDL-C. Il améliore le contrôle glycémique par une augmentation de la sensibilité à l’insuline. Il augmente également le taux d’adiponectine et diminue les marqueurs de l’inflammation. L’ensemble de ces modifications permet de diminuer les risques de maladies cardiovasculaires et de diabète de type 2 qui sont des complications de l’obésité et du syndrome métabolique. Le rimonabant (Acomplia®) a reçu l’autorisation de mise sur le marché en Europe en juin 2006. Cependant, depuis sa commercialisation, de nombreux cas d’effets secondaires psychiatriques (dépressions avec tendances suicidaires) ont été rapportés. La balance bénéfice/risque a été jugée défavorable et a mené au retrait de l’autorisation de mise sur le marché en janvier 2009

Obesity --- Receptor, Cannabinoid, CB1 --- Cannabinoid Receptor Modulators --- rimonabant

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In order to study the bioisosteric replacement oxygen-sulfur, thio-derivatives of 3- alkyl-5,5 '-diphenylirnidazolidin-4-ones - known as selective antagonists of the cannabinoid receptor CB1- were synthezised, giving the 3-alkyl-5,5'-diphenyl-2-thioxo-imidazolidin-4- ones. We have first optimised the synthesis of these thio-derivatives, starting from alkylthioureas and benzils, and using rnicrowaves as activators of the synthesis. Then, the ability of the synthezised compounds to recognize the human cannabinoid receptors CB1 and CB2 has been evaluated. The results, expressed as inhibition constant values (Ki), are promising : the affmity enhancement, compared to the 3-alkyl-5,5'-diphenylimidazolidin-4- ones, is approximately 0.6 units of pKi. Furthermore, these compounds are selective for the CB1 receptor. The compounds possessing the best affinities are those with a para-bromo substituant at the 5,5' phenyls and bearing a short alkyl chain (up to 4 carbons) in position 3. Dans le but d'étudier la bioisostérie oxygène-soufre, des dérivés soufrés des 3-alkyl- 5 5·-diphénylimidazol idin-4-ones - connus pour présenter un antagonisme sélectif pour les cepteurs cannabinoïdes CB1 - ont été synthétisés, menant ainsi aux 3-alkyl-5,5'-diphényl-2- thioxo-imidazolidin-4-ones. Dans un premier temps, nous avons cherché à développer une voie de synthèse optimale pour former ces dérivés soufrés, partant d'alkylthiourée et de benzile, et utilisant les micro-ondes comme activateurs de synthèse. Puis, dans un second temps, la capacité des molécules synthétisées à reconnaître les récepteurs cannabinoïdes CB1et CB humains a été évaluée. Les résultats, exprimés en terme de constante d'inhibition (Ki),sont e2ncourageants : le gain, non négligeable, en affinité, par rapport aux 3-alkyl-5,5'-diphénylimidazolidin-4-ones, est de l'ordre de 0.6 unités de pKi. De plus, ces dérivés présentent une sélectivité pour les récepteurs CB1. Les composés présentant les meilleures affinités sont ceux substitués par un atome de brome en para des phényles en position 5 du cycle et possédant une cha"me alkyle courte Gusqu'à 4 carbones) en position 3.

Receptor, Cannabinoid, CB1 --- Radioligand Assay --- Thiohydantoins --- Thiohydantoins --- Imidazolidines --- Receptor, Cannabinoid, CB2

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During the last 60 years the relevance of cannabis (Cannabis sativa or Cannabis indica) ingredients, like the psychoactive Δ9-tetrahydrocannabinol (THC), cannabidiol, 120+ additional cannabinoids and 440+ non-cannabinoid compounds, for human health and disease has become apparent. Approximately 30 years after the elucidation of THC structure the molecular reasons for the biological activity of these plant extracts were made clearer by the discovery of endocannabinoids, that are endogenous lipids able to bind to the same receptors activated by THC. Besides endocannabinoids, that include several N-acylethanolamines and acylesters, a complex array of receptors, metabolic enzymes, transporters (transmembrane, intracellular and extracellular carriers) were also discovered, and altogether they form a so-called “endocannabinoid system” that has been shown to finely tune the manifold biological activities of these lipid signals. Both plant-derived cannabinoids and endocannabinoids were first discovered by the group led by Prof. Dr. Raphael Mechoulam, who has just celebrated his 90th birthday and clearly stood out as a giant of modern science. The many implications of his seminal work for chemistry, biochemistry, biology, pharmacology and medicine are described in this special issue by the scientists who reached during the last 20 years the highest recognition in the field of (endo)cannabinoid research, receiving the Mechoulam Award for their major contributions. I thank them for having accepted my invitation to be part of this honorary issue of Molecules, and Raphi for continuing to illuminate our field with his always inspiring investigations and new ideas.

Research & information: general --- Biology, life sciences --- Biochemistry --- cannabinoid --- MRI-1867 --- hybrid ligand --- CB1 receptor antagonist --- iNOS inhibitor --- rimonabant --- intracerebroventricular administration --- alcohol craving --- two-bottle paradigm --- drinking in the dark --- N-acyltransferase --- anandamide --- endocannabinoid --- phospholipase A2 --- cannabichromene --- cannabidiolic acid --- cannabidivarin --- cannabidivarinic acid --- phytocannabinoids --- tetrahydrocannabivarin --- 4′-fluoro-cannabidiol --- cannabinoid tetrad --- elevated plus maze --- catalepsy --- marble bury --- HUF-101 --- equilibrative nucleoside transporter --- CB1 --- biased signaling --- functional selectivity --- G-protein --- β-arrestin --- cannabigerol --- anti-inflammatory --- obesity --- cannabinoid receptor 2 (CB2R) --- microglia --- inflammaging --- memory --- lipofuscin --- aminoalkylindole --- allodynia --- antinociception --- cannabinoid receptor --- CP55940 --- JWH-018 --- K2 --- pravadoline --- spice --- WIN55212-2 --- type 1 cannabinoid receptor CB1 --- cholesterol --- hippocampus --- frontal cortex --- synaptosomes --- rescue model --- anti-CB1 antibody --- cannabinoids --- GPR55 receptors --- VCE-006.1 --- chromenopyrazole --- Parkinson’s disease --- 6-hydroxydopamine --- lipopolysaccharide --- amyotrophic lateral sclerosis --- mSOD1 mice --- TDP-43 transgenic mice --- PPARs --- gut microbiome --- intestine --- ghrelin --- LEAP2 --- n/a --- 4'-fluoro-cannabidiol --- Parkinson's disease

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During the last 60 years the relevance of cannabis (Cannabis sativa or Cannabis indica) ingredients, like the psychoactive Δ9-tetrahydrocannabinol (THC), cannabidiol, 120+ additional cannabinoids and 440+ non-cannabinoid compounds, for human health and disease has become apparent. Approximately 30 years after the elucidation of THC structure the molecular reasons for the biological activity of these plant extracts were made clearer by the discovery of endocannabinoids, that are endogenous lipids able to bind to the same receptors activated by THC. Besides endocannabinoids, that include several N-acylethanolamines and acylesters, a complex array of receptors, metabolic enzymes, transporters (transmembrane, intracellular and extracellular carriers) were also discovered, and altogether they form a so-called “endocannabinoid system” that has been shown to finely tune the manifold biological activities of these lipid signals. Both plant-derived cannabinoids and endocannabinoids were first discovered by the group led by Prof. Dr. Raphael Mechoulam, who has just celebrated his 90th birthday and clearly stood out as a giant of modern science. The many implications of his seminal work for chemistry, biochemistry, biology, pharmacology and medicine are described in this special issue by the scientists who reached during the last 20 years the highest recognition in the field of (endo)cannabinoid research, receiving the Mechoulam Award for their major contributions. I thank them for having accepted my invitation to be part of this honorary issue of Molecules, and Raphi for continuing to illuminate our field with his always inspiring investigations and new ideas.

Research & information: general --- Biology, life sciences --- Biochemistry --- cannabinoid --- MRI-1867 --- hybrid ligand --- CB1 receptor antagonist --- iNOS inhibitor --- rimonabant --- intracerebroventricular administration --- alcohol craving --- two-bottle paradigm --- drinking in the dark --- N-acyltransferase --- anandamide --- endocannabinoid --- phospholipase A2 --- cannabichromene --- cannabidiolic acid --- cannabidivarin --- cannabidivarinic acid --- phytocannabinoids --- tetrahydrocannabivarin --- 4'-fluoro-cannabidiol --- cannabinoid tetrad --- elevated plus maze --- catalepsy --- marble bury --- HUF-101 --- equilibrative nucleoside transporter --- CB1 --- biased signaling --- functional selectivity --- G-protein --- β-arrestin --- cannabigerol --- anti-inflammatory --- obesity --- cannabinoid receptor 2 (CB2R) --- microglia --- inflammaging --- memory --- lipofuscin --- aminoalkylindole --- allodynia --- antinociception --- cannabinoid receptor --- CP55940 --- JWH-018 --- K2 --- pravadoline --- spice --- WIN55212-2 --- type 1 cannabinoid receptor CB1 --- cholesterol --- hippocampus --- frontal cortex --- synaptosomes --- rescue model --- anti-CB1 antibody --- cannabinoids --- GPR55 receptors --- VCE-006.1 --- chromenopyrazole --- Parkinson's disease --- 6-hydroxydopamine --- lipopolysaccharide --- amyotrophic lateral sclerosis --- mSOD1 mice --- TDP-43 transgenic mice --- PPARs --- gut microbiome --- intestine --- ghrelin --- LEAP2 --- cannabinoid --- MRI-1867 --- hybrid ligand --- CB1 receptor antagonist --- iNOS inhibitor --- rimonabant --- intracerebroventricular administration --- alcohol craving --- two-bottle paradigm --- drinking in the dark --- N-acyltransferase --- anandamide --- endocannabinoid --- phospholipase A2 --- cannabichromene --- cannabidiolic acid --- cannabidivarin --- cannabidivarinic acid --- phytocannabinoids --- tetrahydrocannabivarin --- 4'-fluoro-cannabidiol --- cannabinoid tetrad --- elevated plus maze --- catalepsy --- marble bury --- HUF-101 --- equilibrative nucleoside transporter --- CB1 --- biased signaling --- functional selectivity --- G-protein --- β-arrestin --- cannabigerol --- anti-inflammatory --- obesity --- cannabinoid receptor 2 (CB2R) --- microglia --- inflammaging --- memory --- lipofuscin --- aminoalkylindole --- allodynia --- antinociception --- cannabinoid receptor --- CP55940 --- JWH-018 --- K2 --- pravadoline --- spice --- WIN55212-2 --- type 1 cannabinoid receptor CB1 --- cholesterol --- hippocampus --- frontal cortex --- synaptosomes --- rescue model --- anti-CB1 antibody --- cannabinoids --- GPR55 receptors --- VCE-006.1 --- chromenopyrazole --- Parkinson's disease --- 6-hydroxydopamine --- lipopolysaccharide --- amyotrophic lateral sclerosis --- mSOD1 mice --- TDP-43 transgenic mice --- PPARs --- gut microbiome --- intestine --- ghrelin --- LEAP2