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These last years, the elucidation of the physiological roles of the anandamide and the 2-arachidonoylglycérol, two endogenous molecules derived from the arachidonic acid, made it possible to highlight a system of neurotransmission called endocannabinoid system. Among the known enzymes of the endocannabinoid system, MonoGlycerol Lipase (MGL) is one of the less characterised. It is a serine hydrolase which is responsible for the degradation of the major endocannabinoid in the central nervous system, the 2-arachidonoylglycerol (2-AG). Several studies highlighted the pharmacological properties of 2-AG, like the inhibition of the proliferation of cancerous cells of breast and prostate, the stimulation of appetite, and a neuroprotector effect following central lesions. To block the MGL would make it possible to increase the rates of 2-AG and by there, to benefit from its pharmacological properties from the therapeutic point of view such as cancer, neuroprotection and anxiety. Nevertheless, few inhibitors of MGL are known to date. My studies consist on the screening of a library of various molecules in a hydrolysis assay of a radiolabelled substrate (2-oleoylglycérol, 2-OG) by the recombining MGL human in order to identify possible inhibitors of MGL and to highlight structure-activity relationships. Secondly, to appreciate the inhibition of active compound discovered by screening, the curves of inhibition have been realized. The pIC50 of several compounds have been determined and vary between 4,46 and 6,45. In a third time, the most potent compound of each groups were tested on intact glioma cells. This last evaluation, has been realized to know if these compound were able to modify the metabolism of 2-OG by intact cells. These different steps performed to identify three groups of chemical structures favourable for the inhibition of MGL: thioamides, phenyl maleimides and disulfides. Ces dernières années, l’élucidation des rôles physiologiques de l’anandamide et du 2-arachidonoylglycérol, deux molécules endogènes dérivées de l’acide arachidonique, a permis de mettre en évidence un système de neurotransmission appelé système endocannabinoïde. Parmi les enzymes connues du système endocannabinoïde, la Monoglycérol Lipase (MGL) est une des moins caractérisées. Il s’agit d’une sérine hydrolase responsable de la dégradation de l’endocannabinoïde majeur dans le système nerveux central, le 2-arachidonoylglycérol (2-AG). Les propriétés pharmacologiques de ce dernier comprennent l’inhibition de la prolifération des cellules cancéreuses du sein et de la prostate, la stimulation de l’appétit et un effet neuroprotecteur suite à des lésions centrales. La MGL dégrade le 2-AG par clivage de son lien ester donnant respectivement le glycérol et l’acide arachidonique. Bloquer la MGL permettrait d’augmenter les taux de 2-AG et par là, profiter de ses propriétés pharmacologiques dans des perspectives thérapeutiques tels que le cancer, la neuroprotection et l’anxiété. Néanmoins, peu d’inhibiteurs de la MGL sont connus à ce jour. C’est dans ce contexte de recherche que s’inscrit mon mémoire. Il consiste au criblage d’une librairie de molécules chimiques dans un test d’hydrolyse d’un substrat radiomarqué (le 2-oléoylglycérol, 2-OG) par la MGL recombinante humaine afin d’identifier d’éventuels inhibiteurs et de tenter de mettre en évidence un lien entre structure et activité. Trois groupes de structures ont été identifiés parmi la large chimiothèque testée. Deuxièmement, afin d’apprécier la puissance des composés les plus actifs, des courbes de détermination d’IC50 ont été réalisées. Les pIC50 de plusieurs composés sont ainsi connus et varient entre 4,46 et 6,45. Dans un troisième temps, les composés les plus puissants de chacun des trois groupes ont été testés sur des cultures de gliomes. Cette dernière évaluation a permis d’évaluer si ces composés étaient capables de modifier le métabolisme du 2-OG par les cellules intactes. Ces différentes étapes ont permis de mettre en évidence trois groupes de molécules présentant un squelette de base propice à l’inhibition de la MGL : les thioamides, les maléimides et les disulfides.
Lipase --- Cannabis --- Hydrolases --- Monoglycerides
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Fitz-Hugh Ludlow was a recent graduate of Union College in Schenectady, New York, when he vividly recorded his hasheesh-induced visions, experiences, adventures, and insights. During the mid-nineteenth century, the drug was a legal remedy for lockjaw and Ludlow had a friend at school from whom he received a ready supply. He consumed such large quantities at each sitting that his hallucinations have been likened to those experienced by opium addicts. Throughout the book, Ludlow colorfully describes his psychedelic journey that led to extended reflections on religion, philosophy, medicine, and culture. First published in 1857, The Hasheesh Eater was the first full-length American example of drug literature. Yet despite the scandal that surrounded it, the book quickly became a huge success. Since then, it has become a cult classic, first among Beat writers in the 1950's and 1960's, and later with San Francisco Bay area hippies in the 1970's. In this first scholarly edition, editor Stephen Rachman positions Ludlow's enduring work as not just a chronicle of drug use but also as a window into the budding American bohemian literary scene. A lucid introduction explores the breadth of Ludlow's classical learning as well as his involvement with the nineteenth-century subculture that included fellow revelers such as Walt Whitman and the pianist Louis Gottshalk. With helpful annotations guiding readers through the text's richly allusive qualities and abundance of references, this edition is ideal for classroom use as well as for general readers.
Cannabis. --- American literature. --- Cannabis gigantea --- Cannabis indica --- Cannabis sativa --- Gallow grass --- Cannabaceae --- Marijuana --- English literature --- Agrarians (Group of writers)
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This book aims to shed light on the current debates of cannabis by reviewing all the available evidence on a range of issues relating to the use of cannabis among children and adolescents and summarizing the main conclusions in clear, jargon-free language.
Marijuana. --- Youth --- Drugs and youth --- Narcotics and youth --- Ganja --- Marihuana --- Weed (Marijuana) --- Cannabis --- Drug use.
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Drugs are part of every society, consumed for ritual or religious purposes, for pleasure, to enhance athletic performance, or as a means to relieve pain. Throughout the twentieth century, however, an arbitrary and shifting distinction was made between legal drugs that were prescribed and administered by the medical profession, and illegal drugs that were subject to state control and suppression. Illegal in Canada since 1923, marijuana is the most controversial of illegal drugs. Because it lacks the same addictive and harmful qualities of other illegal substances, such as heroin and cocaine, marijuana's negative social impact is questionable. In the 1960s interest groups - including university student associations, certain physicians, and others -, began demanding changes to the Narcotics Control Act, which governed the legal status of drugs, to decriminalize or legalize the possession of marijuana. In Not This Time, Marcel Martel explores recreational use of marijuana in the 1960s and its emergence as a topic of social debate. He demonstrates how the media, interest groups, state institutions, bureaucrats and politicians influenced the development and implementation of public policy on drugs. Martel illustrates how two loose coalitions both made up of interest groups, addiction research organizations and bureaucrats - one supporting the existing drug legislation, and the other favoring liberalization of the Narcotics Control Act - dominated the debate over the legalization of marijuana, and how those favoring liberalized drug laws, while influential, had difficulty presenting a unified front and problems justifying their cause while the health benefits of marijuana use were still in question. Exploring both sides of the debate, Martel presents the invigorating history of a question that continues to reverberate in the minds of Canadians. Disclaimer: Images removed at the request of the rights holder.
Marijuana --- Public opinion --- Ganja --- Marihuana --- Weed (Marijuana) --- Cannabis --- Government policy --- History --- Public opinion. --- Canada --- Social policy. --- Politics and government.
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Cannabis --- Plante oléagineuse --- oil crops --- Chanvre --- Hemp --- Plante à fibres --- Fibre crops --- Pratique culturale --- Cultivation --- Technologie --- technology --- Industrie --- industry --- Utilisation --- uses
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