1.
Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc
2.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service
3.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses
4.
Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH
5.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D
6.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES
7.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure
8.
Receptor antagonist
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A receptor antagonist is a type of receptor ligand or drug that blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor. They are sometimes called blockers, examples include alpha blockers, beta blockers, antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors, biochemical receptors are large protein molecules that can be activated by the binding of a ligand. Receptors can be membrane-bound, occurring on the membrane, or intracellular. Binding occurs as a result of noncovalent interaction between the receptor and its ligand, at locations called the site on the receptor. A receptor may contain one or more binding sites for different ligands, binding to the active site on the receptor regulates receptor activation directly. The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the site or the allosteric site. In addition, antagonists may interact at unique binding sites not normally involved in the regulation of the receptors activity to exert their effects. The term antagonist was originally coined to describe different profiles of drug effects, the biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model and it narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn on a cellular response by binding to the receptor. Antagonists were thought to turn off that response by blocking the receptor from the agonist and this definition also remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. Our understanding of the mechanism of drug-induced receptor activation and receptor theory, the two-state model of receptor activation has given way to multistate models with intermediate conformational states. This means efficacy may actually depend on where that receptor is expressed, by definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor, once bound, however, antagonists inhibit the function of agonists, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist, the potency of an antagonist is usually defined by its half maximal inhibitory concentration IC50 value. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the biological response of an agonist
9.
Cannabinoid receptor
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Cannabinoid receptors are of a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the receptors contain seven transmembrane spanning domains. Cannabinoid receptors are activated by three groups of ligands, endocannabinoids, produced by the mammillary body, plant cannabinoids. All of the endocannabinoids and plant cannabinoids are lipophilic, such as fat soluble compounds, there are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2. The CB1 receptor is expressed mainly in the brain, but also in the lungs, liver, the CB2 receptor is expressed mainly in the immune system and in hematopoietic cells. Mounting evidence suggests there are novel cannabinoid receptors that is, non-CB1 and non-CB2. In 2007, the binding of cannabinoids to the G protein-coupled receptor GPR55 in the brain was described. The protein sequences of CB1 and CB2 receptors are about 44% similar, when only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%. In addition, minor variations in each receptor have been identified, cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. Subtype selective cannabinoids have been developed which theoretically may have advantages for treatment of diseases such as obesity. Cannabinoid receptor type 1 receptors are thought to be one of the most widely expressed G protein-coupled receptors in the brain, endocannabinoids released from the depolarized post-synaptic neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release. They are also found in parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis, a 2004 study suggested that the endocannabinoids and their cannabinoid receptors play a major role during pre- and postnatal development. In another recent study a group of researchers combined stochastic optical reconstruction microscopy, CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes and they are also expressed on peripheral nerve terminals. These receptors play a role in antinociception, or the relief of pain, in the brain, they are mainly expressed by microglial cells, where their role remains unclear. Other molecular biology studies have suggested that the orphan receptor GPR55 should in fact be characterised as a cannabinoid receptor, subsequent studies showed that GPR55 does indeed respond to cannabinoid ligands. GPR119 has been suggested as a fifth possible cannabinoid receptor, cannabinoid receptors are activated by cannabinoids, generated naturally inside the body or introduced into the body as cannabis or a related synthetic compound
10.
Cannabinoid receptor type 1
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The cannabinoid receptor type 1, often abbreviated as CB1, is a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous system. These receptors may exist as homodimers or form heterodimers or other GPCR oligomers when coexpressed with one or more classes of G-protein-coupled receptors, observed heterodimers include A2A–CB1, CB1–D2, OX1–CB1, while many more may only be stable enough to exist in vivo. The CB1 receptor possesses an allosteric binding site. The CB1 receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective, the CB1 receptor is activated by cannabinoids, generated naturally inside the body or introduced into the body as cannabis or a related synthetic compound. Research suggests that the majority of CB1 receptors are coupled through Gi/o proteins, alternatively, in some rare cases CB1 receptor activation may be coupled to Gs proteins, which stimulate adenylate cyclase. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release, the relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type. The CB1 receptor can also be modulated by allosterically synthetic ligands in a positive and negative manner, in vivo exposure to THC impairs long-term potentiation and leads to a reduction of phosphorylated CREB. In summary, CB1 receptor activity has been found to be coupled to ion channels, in the following manner, Positively to inwardly rectifying. Negatively to D-type outward potassium channels Negatively to N-type and P/Q-type calcium channels, the CB1 receptor is encoded by the gene CNR1, located on human chromosome 6. Two transcript variants encoding different isoforms have been described for this gene, CNR1 orthologs have been identified in most mammals. The CB1 receptor is expressed pre-synaptically at both glutaminergic and GABAergic interneurons and, in effect, acts as a neuromodulator to inhibit release of glutamate, repeated administration of receptor agonists may result in receptor internalization and/ or a reduction in receptor protein signalling. The inverse agonist MK-9470 makes it possible to produce in vivo images of the distribution of CB1 receptors in the brain with positron emission tomography. CB1 receptors are expressed most densely in the nervous system and are largely responsible for mediating the effects of cannabinoid binding in the brain. These receptors are located in cornu ammonis pyramidal cells, which are known to release glutamate. Cannabinoids suppress the induction of LTP and LTD in the hippocampus by inhibiting these glutamatergic neurons and these receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. However, a density is found within GABAergic cells. This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, in addition, CB1 receptors in the hippocampus indirectly inhibit the release of acetylcholine. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release, an undetermined complex fractal-based, feedforward network allows the brain to weaken specific synapses while others are enhanced, allowing long-range structure to be formed
11.
Rimonabant
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Rimonabant is an inverse agonist for the cannabinoid receptor CB1 and was the first drug approved in that class. It was first in its class to be approved anywhere in the world, the drug was approved in Brazil in April 2007. In November 2008 an advisory committee in Brazil recommended suspension as well, the EMA approval was withdrawn in January 2009. In 2009 India prohibited the manufacture and sale of the drug, when the EMA reviewed postmarketing surveillance data, it found that the risk of psychiatric disorders in people taking rimonabant was doubled
12.
Inverse agonist
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In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agonist, a prerequisite for an inverse agonist response is that the receptor must have a constitutive level activity in the absence of any ligand. An agonist increases the activity of a receptor above its basal level, the efficacy of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% efficacy. An example of a receptor that possesses basal activity and for which inverse agonists have been identified is the GABAA receptor, Agonists for the GABAA receptor create a sedative effect, whereas inverse agonists have anxiogenic effects or even convulsive effects. Two known endogenous inverse agonists are the Agouti-related peptide and its associated peptide Agouti signalling peptide, both appear naturally in humans, and each binds melanocortin receptors 4 and 1, respectively, with nanomolar affinities. The opioid antagonists naloxone and naltrexone are also partial inverse agonists at mu opioid receptors, office of Medical Education - Courses - IDC105 Principles of Pharmacology. Creighton University School of Medicine - Department of Pharmacology, inverse Agonists, An Illustrated Tutorial Panesar K, Guzman F. Pharmacology Corner
13.
Cannabinoid receptor antagonist
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They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the system led to the development of CB1 receptor antagonists. The first CBR antagonist, rimonabant, was described in 1994, rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has an impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research, cannabidiol, a naturally occurring cannabinoid, is a non-competitive CB1/CB2 receptor antagonist. THCV has also high affinity for CB2 receptors and signals as a partial agonist, for centuries hashish and marijuana from the Indian hemp Cannabis sativa L. have been used for medicinal and recreational purposes. In 1840, Schlesinger S. was apparently the first investigator to obtain an active extract from the leaves and flowers of hemp. A few years later, in 1848, Decourtive E. described the preparation of an extract that on evaporation of the solvent gave a dark resin. In 1964 the main constituent of C. sativa L. Δ9-tetrahydrocannabinol, was isolated and synthesized by Mechoulams laboratory. Two types of receptors, CB1 and CB2, responsible for the effects of THC were discovered and cloned in the early 1990s. Once cannabinoid receptors had been discovered, it became important to whether their agonists occur naturally in the body. This search led to the discovery of the first endogenous cannabinoid, later on other endocannabinoids were found, for example 2-AG. These findings raised questions about the pharmacological and physiological role of the cannabinoid system. This revived the research on cannabinoid receptor antagonists which were expected to answer these questions. The use of the cannabinoid agonist, THC, in its preparations to enhance appetite is a well known fact. This fact led to the extension that blocking of the cannabinoid receptors might be useful in decreasing appetite. It was then discovered that the blockage of the CB1 receptor represented a new pharmacological target, the first specific CB1 receptor antagonist / inverse agonist was rimonabant, discovered in 1994. The endogenous cannabinoid system includes cannabinoid receptors, their endogenous ligands and enzymes for their synthesis, there are two main receptor types associated with the endocannabinoid signaling system, cannabinoid receptor 1 and 2
14.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
15.
Cannabinoid
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A cannabinoid is one of a class of diverse chemical compounds that acts on cannabinoid receptors in cells that alter neurotransmitter release in the brain. Ligands for these proteins include the endocannabinoids, the phytocannabinoids. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol, the psychoactive compound in cannabis. Cannabidiol is another constituent of the plant. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied effects, the discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have found in mammals, birds, fish. At present, there are two types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more. The human brain has more cannabinoid receptors than any other G protein-coupled receptor type, CB1 receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain responsible for respiratory. CB1 is also found in the anterior eye and retina. CB2 receptors are found in the immune system, or immune-derived cells with the greatest density in the spleen. While found only in the nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis seen in animal models, the classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 113 different cannabinoids have been isolated from the Cannabis plant To the right, the best studied cannabinoids include tetrahydrocannabinol, cannabidiol and cannabinol. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized, the classical cannabinoids are derived from their respective 2-carboxylic acids by decarboxylation. CBG CBC CBL CBV THCV CBDV CBCV CBGV CBGM THC THCA CBD CBDA Tetrahydrocannabinol is the psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol and delta-8-tetrahydrocannabinol, mimic the actions of anandamide and 2-arachidonoylglycerol neurotransmitters produced naturally in the body and these cannabinoids produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain
16.
Echinacea
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Echinacea /ˌɛkᵻˈneɪʃiə/ is a genus, or group of herbaceous flowering plants in the daisy family. The Echinacea genus has nine species, which are commonly called purple coneflowers and they are found only in eastern and central North America, where they are found growing in moist to dry prairies and open wooded areas. They have large, showy heads of flowers, blooming from early to late summer. The generic name is derived from the Greek word ἐχῖνος, meaning hedgehog and these flowering plants and their parts have different uses. Some species are cultivated in gardens for their showy flowers, Echinacea purpurea is used in folk medicine. Two of the species, E. tennesseensis and E. laevigata, are listed in the United States as endangered species, the DNA analysis allows researchers to reveal clear distinctions among species based on chemical differences in root metabolites. The research concluded that of the 40 genetically diverse populations of Echinacea studied, Echinacea species are herbaceous, drought-tolerant perennial plants growing up to 140 cm or 4 feet, in height. They grow from taproots, except E. purpurea, which grows from a caudex with fibrous roots. They have erect stems that in most species are unbranched, both the basal and cauline leaves are arranged alternately. The leaves are hairy with a rough texture, having uniseriate trichomes but sometimes they lack hairs. The basal leaves and the stem leaves have petioles. The leaf blades in different species may have one, three or five nerves, some species have linear to lanceolate leaves, and others have elliptic- to ovate-shaped leaves, often the leaves decrease in size as they progress up the stems. Leaf bases gradually increase in width away from the petioles or the bases are rounded to heart shaped, most species have leaf margins that are entire, but sometimes they are dentate or serrate. The flowers are collected together into single rounded heads at the ends of long peduncles, the inflorescences have crateriform to hemispheric shaped involucres which are 12–40 mm wide. The phyllaries, or bracts below the head, are persistent. The phyllaries are produced in a 2–4 series, the receptacles are hemispheric to conic. The paleae have orange to reddish purple ends, and are longer than the disc corollas, the paleae bases partially surrounding the cypselae, and are keeled with the apices abruptly constricted to awn-like tips. The ray florets number 8–21 and the corollas are purple to pale pink, white
17.
Caryophyllene
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It is usually found as a mixture with isocaryophyllene and α-humulene, a ring-opened isomer. Caryophyllene is notable for having a ring, as well as a trans-double bond in an 8-membered ring. The first total synthesis of caryophyllene in 1964 by E. J, corey was considered one of the classic demonstrations of the possibilities of synthetic organic chemistry at the time. Caryophyllene is one of the compounds that contributes to the spiciness of black pepper. 14-Hydroxycaryophyllene oxide was isolated from the urine of rabbits treated with -caryophyllene, the x-ray crystal structure of 14-hydroxycaryophyllene has been reported. The metabolism of caryophyllen progresses through -caryophyllene oxide since the compound also afforded 14-hydroxycaryophyllene as a metabolite. Caryophyllene → caryophyllene oxide → 14-hydroxycaryophyllene → 14-hydroxycaryophyllene oxide, caryophyllene oxide, in which the olefin of caryophyllene has become an epoxide, is the component responsible for cannabis identification by drug-sniffing dogs and is also an approved food flavoring. Antinociceptive, neuroprotective, anxiolytic and antidepressant and anti-alcoholism activity in in vitro studies, whether this compound is able to modulate inflammatory processes in humans via the endocannabinoid system is yet unknown. However, it is found to elicit significant neuroprotection by its anti-inflammatory, caryophyllene does not bind to the centrally expressed cannabinoid receptor type-1 and therefore does not exert psychoactive effects. Scientific evidence have been presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC, that could increase its therapeutic index
18.
Cannabichromene
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Cannabichromene is a cannabinoid found in the Cannabis plant and therefore can be also described as a phytocannabinoid - from ancient Greek phyton = plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol and it is actually the second most concentrated cannabinoid in the plant, after tetrahydrocannabinol. Evidence has suggested that it may play a role in the anti-inflammatory and anti-viral effects of cannabis, cannabichromene may contribute to the overall analgesic effects of medical cannabis. A study done in March 2010 showed that CBC along with cannabidiol and tetrahydrocannabinol have antidepressant effects, another study showed that CBC helps promote neurogenesis. CBC is known to interact with receptors in the brain. It is widely known that the cannabinoids interact with the CB1 and CB2 receptors, CBC in particular is known to interact with the TRPV1 and TRPA1 receptors as well, which may result in some of its medicinal properties. Also, in mice, its antiinflammatory activity appears to be modulated by the administration of THC and is independent of the CB2 receptor and this suggests an interplay of the two molecules. It is not scheduled by the Convention on Psychotropic Substances and its boiling point is 220 degrees Celsius,428 degrees Fahrenheit. A study in Neurochemistry International suggested that cannabichromene might stimulate the growth of cells by stimulating adult neural stem progenitor cells. The study said our results suggest that CBC raises the viability of NSPCs while inhibiting their differentiation into astroglia, possibly through up-regulation of ATP, in a 2012 animal study, CBC was shown to normalize gastrointestinal hypermotility without reducing the transit time. The study notes that this is of clinical interest, as the only drugs available for intestinal dysmotility are often associated with constipation. In a 2015 study, CBC, together with other common phytocannabinoids, specifically CBC, cannabidivarin and tetrahydrocannabivarin showed promise to become highly efficient, novel anti-acne agents
19.
Cannabidiol
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Cannabidiol is one of at least 113 active cannabinoids identified in cannabis. It is a major phytocannabinoid, accounting for up to 40% of the plants extract, Dravet syndrome is a rare form of epilepsy that is difficult to treat. It is a form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the year of life other seizure types begin to emerge. A number of profile and anecdotal reports have sparked interest in treatment of Dravet syndrome with cannabidiol. Some cannabis/hemp extract preparations containing CBD are marketed as dietary supplements, one such preparation is marketed under the tradename Charlottes Web Hemp Extract. GW Pharmaceuticals is seeking FDA approval to market a liquid formulation of pure plant-derived CBD, Epidiolex was granted fast-track status and is in late stage trials following positive early results from the drug. A2014 review stated that cannabidiol has been claimed, anecdotally, information in the review stated that there is no established mechanism of action and the lack of high-quality evidence in this area precluded conclusions being drawn. A2016 review states that because of the quality of available data. There is tentative evidence that CBD had an effect. Cannabidiol may also extend the duration of the effects of THC via inhibition of the cytochrome P450 CYP3A, cannabidiol has been found to act as an antagonist of the GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen. It has also shown to act as a 5-HT1A receptor partial agonist, and this action may be involved in the antidepressant, anxiolytic. It is a modulator of the μ and δ-opioid receptors as well. Cannabidiols pharmacological effects have additionally been attributed to PPARγ agonism and intracellular calcium release and it has also been speculated that some of the metabolites of CBD have pharmacological effects that contribute to the biological activity of CBD. Despite this, the evidence in humans suggests no significant effect of CBD on THC plasma levels. Nabiximols is an aerosolized mist for oral administration containing a near 1,1 ratio of CBD, the drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis. Epidiolex, a drug with cannabidiol as its active pharmaceutical ingredient, Epidiolex is an oil formulation of CBD extracted from the cannabis plant undergoing clinical trials for refractory epilepsy syndromes. Cannabidiol is insoluble in water but soluble in solvents such as pentane
20.
Cannabidivarin
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Cannabidivarin is a non-psychoactive cannabinoid found in Cannabis. It is a homolog of cannabidiol, with the side-chain shortened by two methylene bridges, plants with relatively high levels of CBDV have been reported in feral populations of C. indica from northwest India, and in hashish from Nepal. Similarly to CBD, it has 7 double bond isomers and 30 stereoisomers and it is not scheduled by Convention on Psychotropic Substances. It is being developed by GW Pharmaceuticals because of a demonstrated neurochemical pathway for previously-observed anti-epileptic. GW has begun a phase 2 trial for adult epilepsy, and is to begin trials of this CBDV product in children in 2016 in Australia, cannabinoids Cannabis Medical marijuana Erowid Compounds found in Cannabis sativa
21.
Cannabigerol
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Cannabigerol is a non-intoxicating cannabinoid found in the Cannabis genus of plants. CBG is the form of cannabigerolic acid, the parent molecule from which many other cannabinoids are made. CBG has been found to act as a high affinity α2-adrenergic receptor agonist, moderate affinity 5-HT1A receptor antagonist and it also binds to the CB2 receptor as an antagonist. CBG does not trigger THC-like activity in mice, rats, gerbils and non-human primates, moreover, CBG was without effect up to 80 mg/kg in the mouse tetrad test of cannabimimetic activity. It has been shown to improve a model of inflammatory disease, ulcerative colitis. CBG induces production of the natural skin moisturizers, holding promise for dry-skin syndromes. Cannabigerol has been shown to relieve pressure, which may be of benefit in the treatment of glaucoma. CBG has been shown to have properties and may prove promising for the treatment of neurodegenerative diseases such as Huntington’s disease. CBG is known to have properties and research suggests that it might be effective against the superbug MRSA. CBG is showing promising properties in vitro for the treatment of a broad range of cancers including breast, liver, lung, pancreatic, skin, ovarian, renal, bladder. CBG is not scheduled by Convention on Psychotropic Substances, CBG is not scheduled at the federal level in the United States. The biosynthesis of CBG begins by loading a hexanoyl CoA onto a ketide synthetase assembly protein and subsequent condensation with three malonyl CoA molecules
22.
Cannabicyclol
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Cannabicyclol is a non-psychoactive cannabinoid found in Cannabis. CBL is a product like cannabinol. It is not scheduled by Convention on Psychotropic Substances
23.
Cannabinol
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Cannabinol is a psychoactive cannabinoid found only in trace amounts in Cannabis sativa and Cannabis indica. Pharmacologically relevant quantities are formed as a metabolite of tetrahydrocannabinol, CBN acts as a partial agonist at the CB1 receptors, but has a higher affinity to CB2 receptors, however, with lower affinities in comparison to THC. Degraded or oxidized cannabis products, such as low-quality baled cannabis and traditionally produced hashish, are high in CBN, cannabinol has been shown to have analgesic properties. Unlike other cannabinoids, CBN does not stem from cannabigerol but rather is the product of THC. If cannabis is exposed to air or ultraviolet light for a period of time. CBN is then formed by decarboxylation of CBNA, in contrast to THC, CBN has no double bond isomers nor stereoisomers. Both THC and CBN activate the CB1 and CB2 receptors, CBN is not listed in the list of scheduled controlled substances in the USA. It is also possible that CBN may not meet the standard of an analogue for the purposes of bringing forth a prosecution under the Federal Analogue Act. Erowid Compounds found in Cannabis sativa
24.
Tetrahydrocannabinol
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Tetrahydrocannabinol, or more precisely its main isomer -trans-Δ⁹-tetrahydrocannabinol, is the principal psychoactive constituent of cannabis. It can be a clear, amber or gold colored glassy solid when cold, like most pharmacologically-active secondary metabolites of plants, THC in Cannabis is assumed to be involved in self-defense, perhaps against herbivores. THC also possesses high UV-B absorption properties, which, it has been speculated, THC, along with its double bond isomers and their stereoisomers, is one of only three cannabinoids scheduled by the UN Convention on Psychotropic Substances. It was listed under Schedule I in 1971, but reclassified to Schedule II in 1991 following a recommendation from the WHO, based on subsequent studies, the WHO has recommended the reclassification to the less-stringent Schedule III. Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs and it is specifically still listed under Schedule I by US federal law under the Controlled Substances Act signed by the US Congress in 1970. A pharmaceutical formulation is available by prescription in the U. S. dronabinol is the INN for a pure isomer of THC, -trans-Δ⁹-tetrahydrocannabinol, which is the main isomer found in cannabis. It is used to treat anorexia in people with HIV/AIDS as well as for refractory nausea and it is safe and effective for these uses. An overdose of dronabinol usually presents with lethargy, decreased motor coordination, slurred speech, there was a single death rated by the investigator as possibly related to treatment. This person had a seizure followed by aspiration pneumonia, the paper does not describe whether this was one of the subjects from the epilepsy trials. The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide, THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy, THC is a lipophilic molecule and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue. THC, similarly to cannabidiol, albeit less potently, is an allosteric modulator of the μ-. Due to its agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids. However, this form of tolerance appears to be irregular throughout mouse brain areas, THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is oxidized to 11-nor-9-carboxy-THC. In humans and animals, more than 100 metabolites could be identified, metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4. More than 55% of THC is excreted in the feces and ~20% in the urine, the main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected, the discovery of THC, by a team of researchers from Hebrew University Pharmacy School, was first reported in 1964, with substantial later work reported by Raphael Mechoulam in June 1970
25.
Tetrahydrocannabinol-C4
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Tetrahydrocannabinol-C4, also known as THC-C4 and butyl-THC, is a homologue of tetrahydrocannabinol, the active component of cannabis. They are only different by the side chain being replaced by a butyl side chain. It is unknown whether THC-C4 is an agonist, partial agonist, the propyl analog, THCV, is a cannabinoid receptor type 1 and cannabinoid receptor type 2 antagonist, while THC is a CB1 agonist. THC-C4 has rarely been isolated from samples, but appears to be less commonly present than THC or THCV. It is metabolised in a manner to THC. Similarly to THC, it has 7 double bond isomers and 30 stereoisomers and it is not scheduled by Convention on Psychotropic Substances
26.
Tetrahydrocannabinolic acid
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Tetrahydrocannabinolic acid is a biosynthetic precursor of tetrahydrocannabinol, the active component of cannabis. When purified, it forms a crystal which is unstable in the presence of acids, heat, oxygen, THCA does not have any known psychoactive effects on humans in its own right. It does have antiinflammatory, neuroprotective, antiemetic and anti-prostate cancer effects and it inhibits COX-1 and COX-2 enzymes involved in inflammation in human colon cell cultures. It has also shown to decrease the amount of oxidative stress caused by impairment of mitochondria which is a major mechanism in neural degeneration in mouse mesencephalic cell cultures. Despite the ready decarboxylation by drying or heating ex vivo, conversion of THCA to THC in vivo appears to be very limited, consequently, it is believed to be important in less-psychoactive preparations of cannabis used for medical use, such as cannabis tea. THCA is not scheduled by the United Nations Convention on Psychotropic Substances, there is also a practical legal issue of potential THC contamination of THCA which should be considered. As mentioned above, THCA decarboxylates to form THC, a Schedule I controlled substance and this makes it possible that possession of THCA might lead to prosecution for possession of THC due to the presence of THC breakdown products in bulk THCA
27.
Tetrahydrocannabivarin
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Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol having a propyl side chain instead of a pentyl group on the molecule, which makes it produce very different effects from THC. This terpeno-phenolic compound is naturally in Cannabis, sometimes in significant amounts. The psychoactive effects of THCV in Cannabis preparations are not well characterized, similarly to THC, THCV has 7 double bond isomers and 30 stereoisomers. Its melting point is <220 degrees Celsius, <428 degrees Fahrenheit, THCV levels up to 53. 7% of total cannabinoids have been reported. THCV is a cannabinoid receptor type 1 antagonist and cannabinoid receptor type 2 partial agonist, Δ8-THCV has also been shown to be a CB1 antagonist. Both papers describing the properties of THCV were demonstrated in murine models. Unlike THC, cannabidiol, and cannabichromene, THCV doesn’t begin as cannabigerolic acid, instead of combining with olivetolic acid to create CBGA, geranyl pyrophosphate joins with divarinolic acid, which has 2 less carbon atoms. Once CBGVA is created, the process continues exactly the same as it would for THC, CBGVA is broken down to tetrahydrocannabivarin carboxylic acid by the enzyme THCV synthase. At that point, THCVA can be decarboxylated with heat or UV light to create THCV, GW Pharmaceuticals is studying plant-derived tetrahydrocannabivarin for type 2 diabetes in addition to metformin. It is not scheduled by Convention on Psychotropic Substances, cannabinoids Rimonabant Tetrahydrocannabinol-C4 Cannabivarin Parahexyl Cannabis Medical cannabis Erowid Compounds found in Cannabis sativa
28.
Yangonin
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Yangonin is one of the six major kavalactones found in the kava plant. It has been shown to possess binding affinity for the cannabinoid receptor CB1, yangonin displays marked in vitro toxicity on human hepatocytes with approximately 40% reduction in viability based on an ethidium bromide assay. The predominant mode of cell death turned out to be rather than necrosis. No significant changes were observed in glutathione levels
29.
11-Hydroxy-THC
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11-Hydroxy-Δ9-tetrahydrocannabinol is the main active metabolite of Tetrahydrocannabinol which is formed in the body after cannabis is consumed. The conversion from THC to 11-OH-THC is relatively high when cannabis is consumed in the form of cannabis edibles and, compared to oral consumption, 11-OH-THC is more potent than THC and crosses the blood–brain barrier more easily. 11-Hydroxy-THC has been shown to be active in its own right and this might partially explain the biphasic effects of cannabis, whereby some effects such as increased appetite tend to be delayed rather than occurring immediately when the drug is consumed. Fresh cannabis contains Tetrahydrocannabinolic acid, which is converted into THC after heating, 11-Hydroxy-THC is subsequently metabolised further to 11-nor-9-carboxy-THC, which is not psychoactive but might still play a role in the analgesic and anti-inflammatory effects of cannabis
30.
Endocannabinoid
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Two primary endocannabinoid receptors have been identified, CB1, first cloned in 1990, and CB2, cloned in 1993. One other main endocannabinoid is 2-Arachidonoylglycerol which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD, 2-AG and CBD are involved in the regulation of appetite, immune system functions and pain management. The enzymes that synthesize and degrade the endocannabinoids, such as fatty acid amide hydrolase or monoacylglycerol lipase, the cannabinoid receptors CB1 and CB2, two G protein-coupled receptors that are located in the central and peripheral nervous systems. The neurons, neural pathways, and other cells where these molecules, enzymes, the endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators for a variety of processes, including motor learning, appetite, Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain, density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the ganglia and cerebellum. Binding has been demonstrated by 2-arachidonoylglycerol on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response, in addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18, GPR55, and GPR119. During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the cleft which bind to cognate receptors expressed on the post-synaptic neuron. Expression appears to be exclusive, so both types of endocannabinoids are not co-synthesized. Evidence suggests that the influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, experiments have shown that phospholipase D cleaves NAPE to yield anandamide. This process is mediated by bile acids, in NAPE-phospholipase D -knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis. The synthesis of 2-AG is less established and warrants further research, once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, a neuropharmacological study demonstrated that an inhibitor of FAAH selectively increases anandamide levels in the brain of rodents and primates. Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane. The relative potency of different cannabinoids in inhibition of adenylyl cyclase correlates with their varying efficacy in behavioral assays and this inhibition of cAMP is followed by phosphorylation and subsequent activation of not only a suite of MAP kinases, but also the PI3/PKB and MEK/ERK pathway. In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos, the molecular mechanisms of CB1-mediated changes to the membrane voltage have also been studied in detail
31.
2-Arachidonoylglycerol
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2-Arachidonoylglycerol is an endocannabinoid, an endogenous agonist of the CB1 receptor. It is a formed from the omega-6 fatty acid arachidonic acid. It is present at high levels in the central nervous system. It has been found in bovine and human milk. The chemical was first described in 1994-1995, although it had discovered some time before that. The activities of Phospholipase C and diacylglycerol lipase mediate its formation, 2-AG is synthesized from arachidonic acid-containing diacylglycerol. 2-AG, unlike anandamide, is present at high levels in the central nervous system, it is the most abundant molecular species of monoacylglycerol found in mouse. Detection of 2-AG in brain tissue is complicated by the ease of its isomerization to 1-AG during standard lipid extraction conditions. It has been found in maternal bovine as well as human milk, shimon Ben-Shabat, of Ben-Gurion University, discovered the chemical. 2-AG was a chemical compound but its occurrence in mammals. 2-Arachidonoylglycerol, next with Anandamide, was the second endocannabinoid discovered, the cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system. Unlike anandamide, formation of 2-AG is calcium-dependent and is mediated by the activities of phospholipase C, 2-AG acts as a full agonist at the CB1 receptor. At a concentration of 0. 3nM, 2-AG induces a rapid, 2-AG is hydrolyzed in vitro by monoacylglycerol lipase, fatty acid amide hydrolase, and the uncharacterized serine hydrolase enzymes ABHD6 and ABHD12. The exact contribution of each of these enzymes to the termination of 2-AG signaling in vivo is unknown, there have been identified transport proteins for 2-arachidonoylglycerol and anandamide. These include the heat shock proteins and fatty acid binding proteins, 2-Arachidonoylglycerol is synthesized from arachidonic acid-containing diacylglycerol, which is derived from the increase of inositol phospholipid metabolism by the action of diacylglycerol lipase. 2-Arachidonoyl glyceryl ether Endocannabinoid transporters Dinh TP, Carpenter D, Leslie FM, brain monoglyceride lipase participating in endocannabinoid inactivation. Proceedings of the National Academy of Sciences of the United States of America
32.
2-Arachidonyl glyceryl ether
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2-Arachidonyl glyceryl ether is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001. Lumír Hanuš, Saleh Abu-Lafi, Ester Fride, Aviva Breuer, Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and Raphael Mechoulam found the endogenous agonist of the cannabinoid receptor type 1 in 2000. The discovery was 100 gram of porcine brain, was added to a mixture of 200 mL of chloroform and 200 mL of methanol,100 mL of Water was then added, and the mixing process continued for another minute. After this, the mixture was filtered, two layers then formed and the layer of water-methanol was separated and evaporated when pressure was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats, a Hewlett Packard G 1800B GCD system that has a HP-5971 GC with electron ionization detector was used. The production of the endocannabinoid is enhanced in normal, but not in endothelium-denuded rat aorta on reacting with carbachol and it potently reduces blood pressure in rats and may represent an endothelium-derived hypotension factor. 2-Arachidonyl glyceryl ethers structure can be determined by mass spectrometry and Rutherford backscattering spectrometry and it was confirmed by comparison with a synthetic sample of the endocannabinoid. It binds to the Cannabinoid receptor type 1, which causes sedation, hypothermia, intestinal immobility, the endocannabinoid exhibits Ki values of 21.2 nM and >3 µM at the Cannabinoid receptor type 1 and the peripheral cannabinoid receptors. The presence of 2-AGE in body tissue is disputed, 2-AGE binds with a Ki of 21 nM to the CB1 receptor and 480 nM to the CB2 receptor. It shows agonistic behaviour on both receptors and is a partial agonist for the TRPV1 channel, after binding to CB2 receptors it inhibits adenylate cyclase and stimulates ERK-MAPK and regulates calcium transients. In comparison to 2-arachidonoyl glycerol, noladin is metabolically more stable resulting in a longer half-life and it lowers Intraocular pressure, increases the uptake of GABA in the globus pallidus of rats and is neuroprotective by binding to and activation of PPARα. 2-Arachidonoylglycerol Commercial supplier of Noladin ether
33.
2-Oleoylglycerol
–
2-Oleoylglycerol is a monoacylglycerol that is found in biologic tissues. Its synthesis is derived from diacylglycerol precursors and it is metabolized to oleic acid and glycerol primarily by the enzyme monoacylglycerol lipase. In 2011, 2OG was found to be a ligand to GPR119. 2OG has been shown to increase glucagon-like peptide-1 and gastric inhibitory polypeptide levels following administration to the small intestine
34.
N-Arachidonoyl dopamine
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N-Arachidonoyl dopamine is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 ion channel. NADA was first described as a putative endocannabinoid in 2000 and was identified as an endovanilloid in 2002. NADA is an arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum. It activates the TRPV1 channel with an EC50 of approximately of 50nM which makes it the putative endogenous TRPV1 agonist, in mice, NADA was shown to induce the tetrad of physiological paradigms associated with cannabinoids, hypothermia, hypo-locomotion, catalepsy, and analgesia. NADA has been found to play a role in both the peripheral and central nervous systems, and displays antioxidant and neuroprotectant properties. NADA has also implicated in smooth muscle contraction and vasorelaxation in blood vessels. NADA also promotes the inflammatory resolution of human endothelial cells activated by endogenous and exogenous inflammatory mediators. Furthermore, NADA also displays inhibitory activity in HIV-1 replication assays, finally, NADA can prevent the degranulation and release of TNF from RBL- 2H3 mast cells treated with an IgE-antigen complex. Together, theses studies show that physiological functions attributed to NADA are multifaceted, and include the ability to modulate the immune response
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