1.
Nalorphine
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Nalorphine, also known as N-allyl-normorphine, is a mixed opioid agonist–antagonist with opioid antagonist and analgesic properties. It was introduced in 1954 and was used as an antidote to opioid overdose. Nalorphine was the opioid antagonist to be introduced, preceded by nalodeine in 1915 and followed by naloxone in 1960. Due to potent activation of the KOR, nalorphine produces side effects such as dysphoria, anxiety, confusion, and hallucinations, more recently, it has become much more commonplace to use ethyl chloroformate instead of cyanogen bromide for the Von Braun degradation demethylation step. See for example the list of phenyltropanes or the synthesis of paroxetine for further examples of this
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.
ChEMBL
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ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets
5.
European Chemicals Agency
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ECHA is the driving force among regulatory authorities in implementing the EUs chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and it is located in Helsinki, Finland. The Agency, headed by Executive Director Geert Dancet, started working on 1 June 2007, the REACH Regulation requires companies to provide information on the hazards, risks and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most commonly used substances have been registered, the information is technical but gives detail on the impact of each chemical on people and the environment. This also gives European consumers the right to ask whether the goods they buy contain dangerous substances. The Classification, Labelling and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU. This worldwide system makes it easier for workers and consumers to know the effects of chemicals, companies need to notify ECHA of the classification and labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100000 substances, the information is freely available on their website. Consumers can check chemicals in the products they use, Biocidal products include, for example, insect repellents and disinfectants used in hospitals. The Biocidal Products Regulation ensures that there is information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation, the law on Prior Informed Consent sets guidelines for the export and import of hazardous chemicals. Through this mechanism, countries due to hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have effects on human health and the environment are identified as Substances of Very High Concern 1. These are mainly substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment, other substances considered as SVHCs include, for example, endocrine disrupting chemicals. Companies manufacturing or importing articles containing these substances in a concentration above 0 and they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy, once a substance has been officially identified in the EU as being of very high concern, it will be added to a list. This list is available on ECHA’s website and shows consumers and industry which chemicals are identified as SVHCs, Substances placed on the Candidate List can then move to another list
6.
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
7.
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
8.
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
9.
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
10.
Organic compound
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An organic compound is virtually any chemical compound that contains carbon, although a consensus definition remains elusive and likely arbitrary. Organic compounds are rare terrestrially, but of importance because all known life is based on organic compounds. The most basic petrochemicals are considered the building blocks of organic chemistry, for historical reasons discussed below, a few types of carbon-containing compounds, such as carbides, carbonates, simple oxides of carbon, and cyanides are considered inorganic. The distinction between organic and inorganic compounds, while useful in organizing the vast subject of chemistry. Organic chemistry is the science concerned with all aspects of organic compounds, Organic synthesis is the methodology of their preparation. The word organic is historical, dating to the 1st century, for many centuries, Western alchemists believed in vitalism. This is the theory that certain compounds could be synthesized only from their classical elements—earth, water, air, vitalism taught that these organic compounds were fundamentally different from the inorganic compounds that could be obtained from the elements by chemical manipulation. Vitalism survived for a while even after the rise of modern atomic theory and it first came under question in 1824, when Friedrich Wöhler synthesized oxalic acid, a compound known to occur only in living organisms, from cyanogen. A more decisive experiment was Wöhlers 1828 synthesis of urea from the inorganic salts potassium cyanate, urea had long been considered an organic compound, as it was known to occur only in the urine of living organisms. Wöhlers experiments were followed by others, in which increasingly complex organic substances were produced from inorganic ones without the involvement of any living organism. Even though vitalism has been discredited, scientific nomenclature retains the distinction between organic and inorganic compounds, still, even the broadest definition requires excluding alloys that contain carbon, including steel. The C-H definition excludes compounds that are considered organic, neither urea nor oxalic acid is organic by this definition, yet they were two key compounds in the vitalism debate. The IUPAC Blue Book on organic nomenclature specifically mentions urea and oxalic acid, other compounds lacking C-H bonds but traditionally considered organic include benzenehexol, mesoxalic acid, and carbon tetrachloride. Mellitic acid, which contains no C-H bonds, is considered an organic substance in Martian soil. The C-H bond-only rule also leads to somewhat arbitrary divisions in sets of carbon-fluorine compounds, for example, CF4 would be considered by this rule to be inorganic, whereas CF3H would be organic. Organic compounds may be classified in a variety of ways, one major distinction is between natural and synthetic compounds. Another distinction, based on the size of organic compounds, distinguishes between small molecules and polymers, natural compounds refer to those that are produced by plants or animals. Many of these are extracted from natural sources because they would be more expensive to produce artificially
11.
Opioid
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Opioids are substances that act on opioid receptors to produce morphine-like effects. Opioids are most often used medically to relieve pain, and by people addicted to opioids, opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself. Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl, antagonist drugs such as naloxone, the terms opiate and narcotic are sometimes encountered as synonyms for opioid. Opiate is properly limited to the alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives. In some jurisdictions all controlled drugs are classified as narcotics. The term can have pejorative connotations and its use is discouraged where that is the case. Primarily used for relief, including anesthesia they are also used to suppress cough, suppress diarrhea, treat addiction, reverse opioid overdose. Extremely strong opioids are approved only for use such as immobilizing large mammals. Opioids act by binding to receptors, which are found principally in the central and peripheral nervous system. These receptors mediate both the psychoactive and the effects of opioids. The side effects of opioids may include itchiness, sedation, nausea, respiratory depression, constipation, Tolerance and dependence will develop with continuous use, requiring increasing doses and leading to a withdrawal syndrome upon abrupt discontinuation. The euphoria attracts recreational use, and frequent, escalating recreational use of opioids typically results in addiction, accidental overdose or concurrent use with other depressant drugs commonly results in death from respiratory depression. Because of opioid drugs reputation for addiction and fatal overdose, most are controlled substances, illicit production, smuggling, and addiction to opioids prompted treaties, laws and policing which have realized limited success. In 2013 between 28 and 38 million people used opioids illicitly, in 2011 an estimated 4 million people in the United States used opioids recreationally or were dependent on them. Current increased rates of use and addiction are attributed to over-prescription of opioid medications. Conversely, fears about over-prescribing, exaggerated side effects and addiction from opioids are similarly blamed for under-treatment of pain, the term opioid originated in the 1950s. It combines opium + -oid meaning opiate-like, by the late 1960s, research found that opiate effects are mediated by activation of specific molecular receptors in the nervous system, which were termed opioid receptors. The definition of opioid was later refined to refer to substances that have activities that are mediated by the activation of opioid receptors
12.
Analgesic
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An analgesic or painkiller is any member of the group of drugs used to achieve analgesia, relief from pain. Analgesic drugs act in various ways on the peripheral and central nervous systems and they are distinct from anesthetics, which temporarily affect, and in some instances completely eliminate, sensation. Analgesics include paracetamol, the nonsteroidal anti-inflammatory drugs such as the salicylates, when choosing analgesics, the severity and response to other medication determines the choice of agent, the World Health Organization pain ladder specifies mild analgesics as its first step. Topical nonsteroidal anti-inflammatory drugs provided pain relief in common such as muscle sprains. Since the side effects are also lesser, topical preparations could be preferred over oral medications in these conditions, each different type of analgesic has its own associated side effects. Drugs for pain are typically classified by chemical structure and they may also be classified in other ways. Sometimes they are classified by use for classes of medical condition. Other times they are sorted by the needs of populations who would use them. They might be listed by availability in an area, perhaps to prevent recommending a drug which is illegal in one place even if it is easily available elsewhere. Paracetamol, also known as acetaminophen or APAP, is a used to treat pain. It is typically used for mild to moderate pain, in combination with opioid pain medication, paracetamol is used for more severe pain such as cancer pain and after surgery. It is typically used either by mouth or rectally but is also available intravenously, effects last between two and four hours. Paracetamol is classified as a mild analgesic, paracetamol is generally safe at recommended doses. Nonsteroidal anti-inflammatory drugs, are a class that groups together drugs that provide analgesic and antipyretic effects. The most prominent members of group of drugs, aspirin. These drugs have been derived from NSAIDs, the cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least 2 different versions, COX1 and COX2. Research suggested most of the effects of NSAIDs to be mediated by blocking the COX1 enzyme. Thus, the COX2 inhibitors were developed to inhibit only the COX2 enzyme and these drugs are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular
13.
Metazocine
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Metazocine is an opioid analgesic related to pentazocine. Metazocine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN9240 with a 19 gram aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.81 for the hydrochloride and 0.74 for the hydrobromide and it is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in the same fashion as is morphine. The prototype benzomorphan, metazocine, can be obtained from a variation of the morphinan synthesis, thus, reaction of the Grignard reagent from p-methoxybenzyl chloride with the lutidine methiodide affords the benzylated dihydropyridine. Reduction of the enamine π-bond leads to the tetrahydropyridine, cyclization by means of acid leads directly to the benzomorphan ring system. Demethylation of the ring system affords the phenol. Although this last compound is in fact a relatively potent analgesic, phenazocine Pentazocine Cyclazocine Org 6582, a functional MAT inhibitor that is otherwise analogous in structure to the parent compound of article
14.
Sigma receptor
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The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA4503, ditolylguanidine, dimethyltryptamine, and siramesine. However, such drugs had no clinically relevant affinities for μ, κ, however, pharmacological testing indicated that the σ-receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. When the σ1 receptor was isolated and cloned, it was found to have no similarity to the opioid receptors. At this point, they were designated as a class of receptors. The function of these receptors is poorly understood though an endogenous ligand, activation of σ–receptors by an agonist ligand may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be σ–agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, however the exact role of σ–receptors is difficult to establish as many σ–agonists also bind to other targets such as the κ-opioid receptor and the NMDA glutamate receptor. In animal experiments, σ–antagonists such as rimcazole were able to block convulsions from cocaine overdose, σ–antagonists are also under investigation for use as antipsychotic medications. Physiologic effects when the σ–receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, some σ–receptor agonists—such as cocaine, a weak σ–agonist—exert convulsant effects in animals. Behavioral reactions to σ–agonists are rather heterogeneous, some individuals find σ–receptor agonists euphoric with significant anti-depressive effects, other individuals, however, experience dysphoria and often report feelings of malaise or anxiety. Recently selective σ–receptor agonists were shown to produce effects in mice. Sigma Receptor at the US National Library of Medicine Medical Subject Headings
15.
Agonist
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An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, receptors can be activated by either endogenous or exogenous agonists, resulting in a biological response. A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor, an endogenous agonist for a particular receptor is a compound naturally produced by the body that binds to and activates that receptor. For example, the endogenous agonist for serotonin receptors is serotonin, a superagonist is a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%. Full agonists bind and activate a receptor, producing full efficacy at that receptor, one example of a drug that acts as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the nervous system. Partial agonists also bind and activate a receptor, but have only partial efficacy at the receptor relative to a full agonist. Agents like buprenorphine are used to treat opiate dependence for this reason, as they produce milder effects on the receptor with lower dependence. An inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor, inverse agonists exert the opposite pharmacological effect of a receptor agonist, not merely an absence of the agonist effect as seen with antagonist. An example is the inverse agonist rimonabant. A co-agonist works with other co-agonists to produce the desired effect together, NMDA receptor activation requires the binding of both glutamate, glycine and D-serine co-agonists. An irreversible agonist is a type of agonist that binds permanently to a receptor through the formation of covalent bonds, a few of these have been described. A selective agonist is selective for a type of receptor. E. g. buspirone is a selective agonist for serotonin 5-HT1A, terms that describe this phenomenon are functional selectivity, protean agonism, or selective receptor modulators. Potency is the amount of agonist needed to elicit a desired response, the potency of an agonist is inversely related to its EC50 value. The EC50 can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the biological response of the agonist. The EC50 value is useful for comparing the potency of drugs with similar efficacies producing physiologically similar effects, the smaller the EC50 value, the greater the potency of the agonist, the lower the concentration of drug that is required to elicit the maximum biological response. This relationship, termed the index, is defined as the ratio TD50, ED50
16.
Scientific method
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The scientific method is a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry is commonly based on empirical or measurable evidence subject to specific principles of reasoning, experiments need to be designed to test hypotheses. The most important part of the method is the experiment. The scientific method is a process, which usually begins with observations about the natural world. Human beings are naturally inquisitive, so often come up with questions about things they see or hear. The best hypotheses lead to predictions that can be tested in various ways, in general, the strongest tests of hypotheses come from carefully controlled and replicated experiments that gather empirical data. Depending on how well the tests match the predictions, the hypothesis may require refinement. If a particular hypothesis becomes very well supported a theory may be developed. Although procedures vary from one field of inquiry to another, identifiable features are shared in common between them. The overall process of the method involves making conjectures, deriving predictions from them as logical consequences. A hypothesis is a conjecture, based on knowledge obtained while formulating the question, the hypothesis might be very specific or it might be broad. Scientists then test hypotheses by conducting experiments, the purpose of an experiment is to determine whether observations agree with or conflict with the predictions derived from a hypothesis. Experiments can take anywhere from a college lab to CERNs Large Hadron Collider. There are difficulties in a statement of method, however. Though the scientific method is presented as a fixed sequence of steps. Not all steps take place in scientific inquiry, and are not always in the same order. Some philosophers and scientists have argued there is no scientific method, such as Lee Smolin. Nola and Sankey remark that For some, the idea of a theory of scientific method is yester-years debate
17.
Potency (pharmacology)
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In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a response at low concentrations. The potency depends on both the affinity and efficacy, affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level. The response is equal to the effect, or, and depends on both the binding and the drug-bound receptor then producing a response, thus, potency depends on both affinity and efficacy. The agonist, the ligand, drug or hormone that binds to the receptor, the Emax is the maximum possible effect for the agonist. The concentration of A at which E is 50% of Emax is termed the half maximal effective concentration and is abbreviated 50, the term potency refers to the 50 value. The lower the 50, the less the concentration of a drug is required to produce 50% of maximum effect, higher potency does not necessarily mean more side effects. Walker MG, Page CP, Hoffman BF, Curtis M
18.
Hallucinogen
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A hallucinogen is a psychoactive agent which can cause hallucinations, perceptual anomalies, and other substantial subjective changes in thoughts, emotion, and consciousness. The common types of hallucinogens are psychedelics, dissociatives and deliriants, although hallucinations are a common symptom of amphetamine psychosis, amphetamines are not considered hallucinogens, as they are not a primary effect of the drugs themselves. While hallucinations can occur when abusing stimulants, the nature of stimulant psychosis is not unlike delirium, a debate persists on criteria which would easily differentiate a substance which is psychedelic from one hallucinogenic. Sir Thomas Browne in 1646 coined the term hallucination from the Latin word alucinari meaning to wander in the mind, the term psychedelic is derived from the Ancient Greek words psychē and dēloun, or mind-revealing. A hallucinogen and a psychedelic may refer correctly to the same substance, hallucinations and psychedelia may both refer to the same aspects of subjective experience in a given instance. A hallucinogen in this sense refers to any substance which causes changes in perception or hallucinations. In contrast to Hollisters original criteria, adverse effects may predominate with some hallucinogens with this application of the term, the word psychedelic was coined to express the idea of a drug that makes manifest a hidden but real aspect of the mind. One explanatory model for the experiences provoked by psychedelics is the reducing valve concept, in this view, the drugs disable the brains filtering ability to selectively prevent certain perceptions, emotions, memories and thoughts from ever reaching the conscious mind. This effect has been described as mind expanding, or consciousness expanding, many designer drugs and research chemicals are hallucinogenic in nature, such as those in the 2C and NBOMe families. Dissociatives produce analgesia, amnesia and catalepsy at anesthetic doses, dissociative symptoms include the disruption or compartmentalization of. the usually integrated functions of consciousness, memory, identity or perception. p. 523 Dissociation of sensory input can cause derealization, the perception of the world as being dream-like or unreal. The primary dissociatives achieve their effect through blocking the signals received by the NMDA receptor set and include ketamine, methoxetamine, phencyclidine, dextromethorphan, however, dissociation is also remarkably administered by salvinorin As potent κ-opioid receptor agonism. Some dissociatives can have CNS depressant effects, thereby carrying similar risks as opioids, DXM in higher doses can increase heart rate and blood pressure and still depress respiration. Inversely, PCP can have unpredictable effects and has often been classified as a stimulant. While many have reported that they feel no pain while under the effects of PCP, DXM and Ketamine, this does not fall under the usual classification of anesthetics in recreational doses. Rather, true to their name, they process pain as a kind of far away sensation, pain, although present, becomes a disembodied experience, as for probably the most common dissociative, nitrous oxide, the principal risk seems to be due to oxygen deprivation. Injury from falling is also a danger, as nitrous oxide may cause loss of consciousness. Because of the level of physical activity and relative imperviousness to pain induced by PCP
19.
Morphine
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Morphine is a pain medication of the opiate type which is found naturally in a number of plants and animals. It acts directly on the nervous system to decrease the feeling of pain. It can be taken for both pain and chronic pain. Morphine is frequently used for pain from myocardial infarction and during labour and it can be given by mouth, by injection into a muscle, by injecting under the skin, intravenously, into the space around the spinal cord, or rectally. Maximum effect is around 20 min when given intravenously and 60 min when given by mouth while duration of effect is three and seven hours. Potentially serious side effects include a decreased respiratory effort and low blood pressure, morphine has a high potential for addiction and abuse. If the dose is reduced after long-term use, withdrawal may occur, common side effects include drowsiness, vomiting, and constipation. Caution is advised when used during pregnancy or breast feeding, as morphine will affect the baby, morphine was first isolated between 1803 and 1805 by Friedrich Sertürner. This is generally believed to be the first isolation of an ingredient from a plant. Merck began marketing it commercially in 1827, morphine was more widely used after the invention of the hypodermic syringe in 1853–1855. Sertürner originally named the substance morphium after the Greek god of dreams, the primary source of morphine is isolation from poppy straw of the opium poppy. In 2013, an estimated 523,000 kilograms of morphine were produced, about 45,000 kilograms were used directly for pain, an increase over the last twenty years of four times. Most use for this purpose was in the developed world, about 70% of morphine is used to make other opioids such as hydromorphone, oxycodone and heroin. It is a Schedule II drug in the United States, Class A in the United Kingdom and it is on the World Health Organizations List of Essential Medicines, the most effective and safe medicines needed in a health system. Morphine is sold under trade names. Morphine is used primarily to treat both acute and chronic severe pain and it is also used for pain due to myocardial infarction and for labor pains. Its duration of analgesia is about three to seven hours, however, concerns exist that morphine may increase mortality in the setting of non ST elevation myocardial infarction. Morphine has also traditionally used in the treatment of acute pulmonary edema
20.
Enantiomer
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A single chiral atom or similar structural feature in a compound causes that compound to have two possible structures which are non-superposable, each a mirror image of the other. Each member of the pair is termed an enantiomorph, the property is termed enantiomerism. The presence of multiple features in a given compound increases the number of geometric forms possible. Enantiopure compounds refer to samples having, within the limits of detection and they are sometimes called optical isomers for this reason. Enantiomer members often have different chemical reactions with other enantiomer substances, since many biological molecules are enantiomers, there is sometimes a marked difference in the effects of two enantiomers on biological organisms. Owing to this discovery, drugs composed of one enantiomer can be developed to enhance the pharmacological efficacy. An example is eszopiclone, which is enantiopure and therefore administered in doses that are exactly 1/2 of the older, in the case of eszopiclone, the S enantiomer is responsible for all the desired effects, while the other enantiomer seems to be inactive. A dose of 2 mg of zopiclone must be administered to produce the therapeutic effect as 1 mg of eszopiclone. In chemical synthesis of enantiomeric substances, non-enantiomeric precursors inevitably produce racemic mixtures, in the absence of an effective enantiomeric environment, separation of a racemic mixture into its enantiomeric components is impossible. The R/S system is an important nomenclature system for denoting distinct enantiomers, another system is based on prefix notation for optical activity, - and - or d- and l-. The Latin for left and right is laevus and dexter, respectively, left and right have always had moral connotations, and the Latin words for these are sinister and rectus. The English word right is a cognate of rectus and this is the origin of the D, L and S, R notations, and the employment of prefixes levo- and dextro- in common names. Most compounds that one or more asymmetric carbon atoms show enantiomerism. There are a few compounds that do have asymmetric carbon atoms. An example of such an enantiomer is the sedative thalidomide, which was sold in a number of countries across the world from 1957 until 1961 and it was withdrawn from the market when it was found to cause of birth defects. One enantiomer caused the desirable effects, while the other, unavoidably present in equal quantities. The herbicide mecoprop is a mixture, with the --enantiomer possessing the herbicidal activity. Another example is the antidepressant drugs escitalopram and citalopram, citalopram is a racemate, escitalopram is a pure enantiomer
21.
Binding selectivity
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Binding selectivity is defined with respect to the binding of ligands to a substrate forming a complex. A selectivity coefficient is the constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate. Binding selectivity is of importance in biochemistry and in chemical separation processes. The concept of selectivity is used to quantify the extent to which a substrate, A. The simplest case is where the complexes formed have 1,1 stoichiometry, then, the two interactions may be characterized by equilibrium constants KAB and KAC. A + B ↽ − − ⇀ AB, K AB = A + C ↽ − − ⇀ AC, a selectivity coefficient is defined as the ratio of the two equilibrium constants. The greater the selectivity coefficient, the more the ligand C will displace the ligand B from the complex formed with the substrate A, an alternative interpretation is that the greater the selectivity coefficient, the lower the concentration of C that is needed to displace B from AB. Selectivity coefficients are determined experimentally by measuring the two constants, KAB and KAC. In biochemistry the substrate is known as a receptor, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signalling molecules may bind. A ligand may be a peptide or another small molecule, such as a neurotransmitter, a hormone, the specificity of a receptor is determined by its spatial geometry and the way it binds to the ligand through non-covalent interactions, such as hydrogen bonding or Van der Waals forces. If a receptor can be isolated a synthetic drug can be developed either to stimulate the receptor, an agonist or to block it, the stomach ulcer drug cimetidine was developed as an H2 antagonist by chemically engineering the molecule for maximum specificity to an isolated tissue containing the receptor. The further use of quantitative structure-activity relationships led to the development of agents such as ranitidine. It is important to note that selectivity when referring to a drug is relative, for example, in a higher dose, a specific drug molecule may also bind to other receptors than those said to be selective. Chelation therapy is a form of treatment in which a chelating ligand is used to selectively remove a metal from the body. Selectivity is determined by various factors and it also forms stronger complexes with oxygen-donor ligands than with nitrogen-donor ligands. Deferoxamine, a naturally occurring siderophore produced by the actinobacter Streptomyces pilosus and was used initially as a chelation therapy agent, synthetic siderophores such as deferiprone and deferasirox have been developed, using the known structure of deferoxamine as a starting point. Chelation occurs with the two oxygen atoms, wilsons disease is caused by a defect in copper metabolism which results in accumulation of copper metal in various organs of the body. The target ion in this case is divalent, Cu2+ and this ion is classified as borderline in the scheme of Ahrland, Chatt and Davies
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Radiolabel
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Isotopic labeling is a technique used to track the passage of an isotope through a reaction, metabolic pathway, or cell. The reactant is labeled by replacing specific atoms by their isotope, the reactant is then allowed to undergo the reaction. The position of the isotopes in the products is measured to determine the sequence the isotopic atom followed in the reaction or the metabolic pathway. The nuclides used in isotopic labeling may be stable nuclides or radionuclides, in the latter case, the labeling is called radiolabeling. In isotopic labeling, there are ways to detect the presence of labeling isotopes, through their mass, vibrational mode. Mass spectrometry detects the difference in a mass, while infrared spectroscopy detects the difference in the isotopes vibrational modes. Nuclear magnetic resonance detects atoms with different gyromagnetic ratios, the radioactive decay can be detected through an ionization chamber or autoradiographs of gels. An example of the use of isotopic labeling is the study of phenol in water by replacing common hydrogen with deuterium, only the hydroxyl group was affected, indicating that the other 5 hydrogen atoms did not participate in these exchange reactions. An isotopic tracer, is used in chemistry and biochemistry to help understand chemical reactions and interactions, in this technique, one or more of the atoms of the molecule of interest is substituted for an atom of the same chemical element, but of a different isotope. The difference in the number of neutrons, however, means that it can be detected separately from the atoms of the same element. Nuclear magnetic resonance and mass spectrometry are used to investigate the mechanisms of chemical reactions, NMR and MS detects isotopic differences, which allows information about the position of the labeled atoms in the products structure to be determined. With information on the positioning of the atoms in the products. Radioactive isotopes can be tested using the autoradiographs of gels in gel electrophoresis, the radiation emitted by compounds containing the radioactive isotopes darkens a piece of photographic film, recording the position of the labeled compounds relative to one another in the gel. Isotope tracers are used in the form of isotope ratios. Isotopic tracers are some of the most important tools in geology because they can be used to understand complex mixing processes in earth systems, further discussion of the application of isotopic tracers in geology is covered under the heading of isotope geochemistry. Isotopic tracers are usually subdivided into two categories, stable isotope tracers and radiogenic isotope tracers, stable isotope tracers involve only non-radiogenic isotopes and usually are mass-dependent. In theory, any element with two isotopes can be used as an isotopic tracer. However, the most commonly used stable isotope tracers involve relatively light isotopes, a radiogenic isotope tracer involves an isotope produced by radioactive decay, which is usually in a ratio with a non-radiogenic isotope
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Stereoselectivity
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The selectivity arises from differences in steric effects and electronic effects in the mechanistic pathways leading to the different products. Stereoselectivity can vary in degree but it can never be total since the energy difference between the two pathways is finite. However, in cases, the minor stereoisomer may not be detectable by the analytic methods used. The degree of selectivity is measured by the enantiomeric excess, a diastereoselective reaction is one in which one diastereomer is formed in preference to another, establishing a preferred relative stereochemistry. The degree of selectivity is measured by the diastereomeric excess. Stereoconvergence can be considered an opposite of stereoselectivity, when the reaction of two different stereoisomers yield a single product stereoisomer, the quality of stereoselectivity is concerned solely with the products, and their stereochemistry. Of a number of possible products, the reaction selects one or two to be formed. An example of modest stereoselectivity is the dehydrohalogenation of 2-iodo-butane which yields 60% trans-2-butene, since alkene geometric isomers are also classified as diastereomers, this reaction would also be called diastereoselective. The chiral center need not be pure, as the relative stereochemistry will be the same for both enantiomers. In the case of chiral alcohols, kinetic resolution results. Another example is Sharpless asymmetric dihydroxylation, in the example below the achiral alkene yields only one of possible 4 stereoisomers. With a stereogenic center next to the carbocation the substitution can be stereoselective in inter-, the first dirigent protein was discovered in Forsythia intermedia. This protein has found to direct the stereoselective biosynthesis of -pinoresinol from coniferyl alcohol monomers. Recently, a second, enantiocomplementary dirigent protein was identified in Arabidopsis thaliana, stereospecific Dynamic stereochemistry Torquoselectivity Regioselectivity Chemoselectivity
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Pharmacodynamics
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Pharmacodynamics is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms, Pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence dosing, benefit, and adverse effects, Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference. Pharmacodynamics places particular emphasis on relationships, that is, the relationships between drug concentration and effect. One dominant example is drug-receptor interactions as modeled by L + R ⇌ L ⋅ R where L, R, and LR represent ligand, receptor and this equation represents a simplified model of reaction dynamics that can be studied mathematically through tools such as free energy maps. Antacids and chelating agents combine chemically in the body, the widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action, blocked action, in principle, a pharmacologist would aim for a target plasma concentration of the drug for a desired level of response. In reality, there are factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown, genetic factors may exist which would alter metabolism or drug action itself, and a patients immediate status may also affect indicated dosage. The duration of action of a drug is the length of time that particular drug is effective, the binding of ligands to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the concentration of bound receptors. The equilibrium dissociation constant is defined by, L + R ↔ L ⋅ R K d = where L=ligand, R=receptor, the fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear and this explains the so-called receptor reserve phenomenon i. e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. The simplest interpretation of receptor reserve is that it is a model that states there are excess receptors on the surface than what is necessary for full effect. Thus, the existence of receptor reserve depends on the agonist, tissue, as receptor reserve is very sensitive to agonist’s intrinsic efficacy, it is usually defined only for full agonists. Often the response is determined as a function of log to consider many orders of magnitude of concentration, however, there is no biological or physical theory which relates effects to the log of concentration. It is just convenient for graphing purposes and it is useful to note that 50% of the receptors are bound when =Kd. The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion, the curve toward the left represents a higher potency since lower concentrations are needed for a given response
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Ligand (biochemistry)
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In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein, the binding typically results in a change of conformation of the target protein. In DNA-ligand binding studies, the ligand can be a molecule, ion. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure, the instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number. Binding occurs by intermolecular forces, such as bonds, hydrogen bonds. The association of docking is actually reversible through dissociation, measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry, in biochemistry it is whether the ligand generally binds at a metal site. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed, the etymology stems from ligare, which means to bind. Ligand binding to a receptor protein alters the chemical conformation by affecting the shape orientation. The conformation of a receptor protein composes the functional state, ligands include substrates, inhibitors, activators, and neurotransmitters. The rate of binding is called affinity, and this measurement typifies a tendency or strength of the effect, binding affinity is actualized not only by host-guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution. The solvent provides an environment for the ligand and receptor to adapt. Radioligands are radioisotope labeled compounds are used in vivo as tracers in PET studies, the interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity binding results in a degree of occupancy for the ligand at its receptor binding site than is the case for low-affinity binding. A ligand that can bind to a receptor, alter the function of the receptor, high-affinity ligand binding implies that a relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. The lower the Ki concentration is, the more likely there will be a reaction between the pending ion and the receptive antigen. In the example shown to the right, two different ligands bind to the receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, an agonist that can only partially activate the physiological response is called a partial agonist
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Ligand
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In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the electron pairs. The nature of bonding can range from covalent to ionic. Furthermore, the bond order can range from one to three. Ligands are viewed as Lewis bases, although rare cases are known to involve Lewis acidic ligand, metals and metalloids are bound to ligands in virtually all circumstances, although gaseous naked metal ions can be generated in high vacuum. Ligands in a complex dictate the reactivity of the atom, including ligand substitution rates, the reactivity of the ligands themselves. Ligand selection is a consideration in many practical areas, including bioinorganic and medicinal chemistry, homogeneous catalysis. Ligands are classified in many ways, including, charge, size, the identity of the atom. The size of a ligand is indicated by its cone angle, the composition of coordination complexes have been known since the early 1800s, such as Prussian blue and copper vitriol. The key breakthrough occurred when Alfred Werner reconciled formulas and isomers and he showed, among other things, that the formulas of many cobalt and chromium compounds can be understood if the metal has six ligands in an octahedral geometry. The first to use the term ligand were Alfred Stock and Carl Somiesky, the theory allows one to understand the difference between coordinated and ionic chloride in the cobalt ammine chlorides and to explain many of the previously inexplicable isomers. He resolved the first coordination complex called hexol into optical isomers, in general, ligands are viewed as electron donors and the metals as electron acceptors. This is because the ligand and central metal are bonded to one another, bonding is often described using the formalisms of molecular orbital theory. The HOMO can be mainly of ligands or metal character, ligands and metal ions can be ordered in many ways, one ranking system focuses on ligand hardness. Metal ions preferentially bind certain ligands, in general, soft metal ions prefer weak field ligands, whereas hard metal ions prefer strong field ligands. According to the orbital theory, the HOMO of the ligand should have an energy that overlaps with the LUMO of the metal preferential. Metal ions bound to strong-field ligands follow the Aufbau principle, whereas complexes bound to weak-field ligands follow Hunds rule. Binding of the metal with the results in a set of molecular orbitals, where the metal can be identified with a new HOMO and LUMO
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Guinea pig
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The guinea pig, cavy or domestic guinea pig, or cuy for livestock breeds, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family Suidae, recent studies applying molecular markers, in addition to studying the skull and skeletal morphology of current and mummified animals, revealed that the ancestor is most likely Cavia tschudii. Since the 1960s, efforts have made to increase consumption of the animal outside South America. In Western societies, the guinea pig has enjoyed widespread popularity as a household pet since its introduction by European traders in the 16th century. Their docile nature, friendly, even affectionate responsiveness to handling and feeding, biological experimentation on guinea pigs has been carried out since the 17th century. They are still used in research, primarily as models for medical conditions such as juvenile diabetes, tuberculosis, scurvy. The guinea pig was first domesticated as early as 5000 BC for food by tribes in the Andean region of South America, statues dating from circa 500 BC to 500 AD that depict guinea pigs have been unearthed in archaeological digs in Peru and Ecuador. The Moche people of ancient Peru worshipped animals and often depicted the guinea pig in their art, from about 1200 AD to the Spanish conquest in 1532, selective breeding resulted in many varieties of domestic guinea pigs, which form the basis for some of the modern domestic breeds. They continue to be a source in the region, many households in the Andean highlands raise the animal. Folklore traditions involving guinea pigs are numerous, they are exchanged as gifts, used in social and religious ceremonies. They also play a role in healing rituals by folk doctors, or curanderos, who use the animals to diagnose diseases such as jaundice, rheumatism, arthritis. They are rubbed against the bodies of the sick, and are seen as a supernatural medium, black guinea pigs are considered especially useful for diagnoses. The animal also may be cut open and its entrails examined to determine whether the cure was effective and these methods are widely accepted in many parts of the Andes, where Western medicine is either unavailable or distrusted. Spanish, Dutch, and English traders brought guinea pigs to Europe, the guinea pig was first described in the West in 1554 by the Swiss naturalist Conrad Gessner. Its binomial scientific name was first used by Erxleben in 1777, it is an amalgam of Pallas generic designation, the scientific name of the common species is Cavia porcellus, with porcellus being Latin for little pig. Cavia is New Latin, it is derived from cabiai, the name in the language of the Galibi tribes once native to French Guiana. Cabiai may be an adaptation of the Portuguese çavia, which is derived from the Tupi word saujá. Guinea pigs are called quwi or jaca in Quechua and cuy or cuyo in the Spanish of Ecuador, Peru, and Bolivia
28.
Brain
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The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. The brain is located in the head, usually close to the organs for senses such as vision. The brain is the most complex organ in a vertebrates body, in a human, the cerebral cortex contains approximately 15–33 billion neurons, each connected by synapses to several thousand other neurons. Physiologically, the function of the brain is to exert centralized control over the other organs of the body, the brain acts on the rest of the body both by generating patterns of muscle activity and by driving the secretion of chemicals called hormones. This centralized control allows rapid and coordinated responses to changes in the environment, the operations of individual brain cells are now understood in considerable detail but the way they cooperate in ensembles of millions is yet to be solved. This article compares the properties of brains across the range of animal species. It deals with the human brain insofar as it shares the properties of other brains, the ways in which the human brain differs from other brains are covered in the human brain article. Several topics that might be covered here are instead covered there because more can be said about them in a human context. The most important is brain disease and the effects of brain damage, the shape and size of the brain varies greatly between species, and identifying common features is often difficult. Nevertheless, there are a number of principles of architecture that apply across a wide range of species. Some aspects of structure are common to almost the entire range of animal species, others distinguish advanced brains from more primitive ones. The simplest way to gain information about brain anatomy is by visual inspection, Brain tissue in its natural state is too soft to work with, but it can be hardened by immersion in alcohol or other fixatives, and then sliced apart for examination of the interior. Visually, the interior of the consists of areas of so-called grey matter, with a dark color, separated by areas of white matter. Further information can be gained by staining slices of tissue with a variety of chemicals that bring out areas where specific types of molecules are present in high concentrations. It is also possible to examine the microstructure of brain tissue using a microscope, the brains of all species are composed primarily of two broad classes of cells, neurons and glial cells. Glial cells come in types, and perform a number of critical functions, including structural support, metabolic support, insulation. Neurons, however, are considered the most important cells in the brain. The property that makes neurons unique is their ability to send signals to target cells over long distances
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Cell membrane
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The cell membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is permeable to ions and organic molecules and controls the movement of substances in. The basic function of the membrane is to protect the cell from its surroundings. It consists of the bilayer with embedded proteins. Cell membranes can be artificially reassembled, Some authors that did not believe that there was a functional permeable boundary at the surface of the cell preferred to use the term plasmalemma to the extern region of the cell. The cell membrane surrounds the cytoplasm of living cells, physically separating the components from the extracellular environment. The cell membrane also plays a role in anchoring the cytoskeleton to provide shape to the cell, fungi, bacteria, most archaea, and plants also have a cell wall, which provides a mechanical support to the cell and precludes the passage of larger molecules. The cell membrane is permeable and able to regulate what enters and exits the cell. The movement of substances across the membrane can be passive, occurring without the input of cellular energy, or active. The membrane also maintains the cell potential, the cell membrane thus works as a selective filter that allows only certain things to come inside or go outside the cell. The cell employs a number of mechanisms that involve biological membranes,1. Passive osmosis and diffusion, Some substances such as carbon dioxide and oxygen, can move across the membrane by diffusion. Because the membrane acts as a barrier for certain molecules and ions, such a concentration gradient across a semipermeable membrane sets up an osmotic flow for the water. Transmembrane protein channels and transporters, Nutrients, such as sugars or amino acids, must enter the cell, such molecules diffuse passively through protein channels such as aquaporins in facilitated diffusion or are pumped across the membrane by transmembrane transporters. Protein channel proteins, also called permeases, are quite specific, recognizing and transporting only a limited food group of chemical substances. Endocytosis, Endocytosis is the process in which cells absorb molecules by engulfing them, the plasma membrane creates a small deformation inward, called an invagination, in which the substance to be transported is captured. The deformation then pinches off from the membrane on the inside of the cell, Endocytosis is a pathway for internalizing solid particles, small molecules and ions, and macromolecules. Endocytosis requires energy and is thus a form of active transport and this is the process of exocytosis
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Intrinsic activity
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Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This use of the efficacy was introduced by Stephenson to describe the way in which agonists vary in the response they produce. High efficacy agonists can produce the maximal response of the system while occupying a relatively low proportion of the receptors in that system. Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, since the observed response may be less than maximal in systems with no spare receptor reserve, some low efficacy agonists are referred to as partial agonists. Similarly many antagonists are in fact partial agonists or inverse agonists, compounds considered partial agonists tend to have efficacy in between this range
31.
Mouse
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A mouse is a small rodent characteristically having a pointed snout, small rounded ears, a body-length scaly tail and a high breeding rate. The best known species is the common house mouse. It is also a popular pet, in some places, certain kinds of field mice are locally common. They are known to invade homes for food and shelter, domestic mice sold as pets often differ substantially in size from the common house mouse. This is attributable both to breeding and to different conditions in the wild, the most well known strain, the white lab mouse, has more uniform traits that are appropriate to its use in research. The American white-footed mouse and the mouse, as well as other common species of mouse-like rodents around the world. These, however, are in other genera, cats, wild dogs, foxes, birds of prey, snakes and even certain kinds of arthropods have been known to prey heavily upon mice. Nevertheless, because of its adaptability to almost any environment. Mice, in contexts, can be considered vermin which are a major source of crop damage, causing structural damage. In North America, breathing dust that has come in contact with mouse excrement has been linked to hantavirus, primarily nocturnal animals, mice compensate for their poor eyesight with a keen sense of hearing, and rely especially on their sense of smell to locate food and avoid predators. Mice build intricate burrows in the wild and these burrows typically have long entrances and are equipped with escape tunnels or routes. In at least one species, the design of a burrow is a genetic trait. Breeding onset is at about 50 days of age in females and males, although females may have their first estrus at 25–40 days. Mice are polyestrous and breed year round, ovulation is spontaneous, the duration of the estrous cycle is 4–5 days and estrus itself lasts about 12 hours, occurring in the evening. Vaginal smears are useful in timed matings to determine the stage of the estrous cycle, mating is usually nocturnal and may be confirmed by the presence of a copulatory plug in the vagina up to 24 hours post-copulation. The presence of sperm on a smear is also a reliable indicator of mating. Female mice housed together tend to go into anestrus and do not cycle, if exposed to a male mouse or the pheromones of a male mouse, most of the females will go into estrus in about 72 hours. This synchronization of the cycle is known as the Whitten effect
32.
HEK 293 cells
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HEK293 cells have been widely used in cell biology research for many years, because of their reliable growth and propensity for transfection. They are also used by the industry to produce therapeutic proteins. HEK293 cells were generated in 1973 by transformation of cultures of human embryonic kidney cells with sheared adenovirus 5 DNA in Alex van der Ebs laboratory in Leiden. The cells were obtained from a single, apparently healthy, legally aborted fetus under Dutch law, the identity of the mother, the cells were cultured by van der Eb, the transformation by adenovirus was performed by Frank Graham, a post-doc in van der Ebs lab. They were published in 1977 after Graham left Leiden for McMaster University, Graham performed the transformation a total of eight times, obtaining just one clone of cells that were cultured for several months. After presumably adapting to culture, cells from this clone developed into the relatively stable HEK293 line. Subsequent analysis has shown that the transformation was brought about by inserting ~4.5 kilobases from the arm of the viral genome. For many years it was assumed that HEK293 cells were generated by transformation of either a fibroblastic, however, the original adenovirus transformation was inefficient, suggesting that the cell that finally produced the HEK293 line may have been unusual in some fashion. The HEK293 pattern most closely resembled that of adrenal cells, given the location of the adrenal gland, a few adrenal cells could plausibly have appeared in an embryonic kidney derived culture, and could be preferentially transformed by adenovirus. Adenovirus transforms neuronal lineage cells much more efficiently than typical human kidney epithelial cells, an embryonic adrenal precursor cell therefore seems the most likely origin cell of the HEK293 line. As a consequence, HEK293 cells should not be used as an in vitro model of typical kidney cells, HEK293 cells have a complex karyotype, exhibiting two or more copies of each chromosome and with a modal chromosome number of 64. They are described as hypotriploid, containing less than three times the number of chromosomes of a normal human cell. Chromosomal abnormalities include a total of three copies of the X chromosome and four copies of chromosome 17 and chromosome 22, the presence of multiple X chromosomes and the lack of any trace of Y chromosome derived sequence suggest that the source fetus was female. HEK293 cells are straightforward to grow in culture and to transfect and they have been used as hosts for gene expression. Typically, these experiments involve transfecting in a gene of interest, the widespread use of this cell line is due to its transfectability by the various techniques, including calcium phosphate method, achieving efficiencies approaching 100%. Viruses offer an efficient means of delivering genes into cells, which evolved to do. However, as pathogens, they present a risk to the experimenter. This danger can be avoided by the use of viruses which lack key genes, in order to propagate such viral vectors, a cell line that expresses the missing genes is required
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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
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IC50
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The half maximal inhibitory concentration is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a drug or other substance is needed to inhibit a given biological process by half. The values are expressed as molar concentration. It is commonly used as a measure of antagonist drug potency in pharmacological research, according to the FDA, IC50 represents the concentration of a drug that is required for 50% inhibition in vitro. It is comparable to an EC50 for agonist drugs, EC50 also represents the plasma concentration required for obtaining 50% of a maximum effect in vivo. The IC50 of a drug can be determined by constructing a dose-response curve, IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. IC50 values can be used to compare the potency of two antagonists, IC50 values are very dependent on conditions under which they are measured. In general, the higher the concentration of inhibitor, the more agonist activity will be lowered, IC50 value increases as agonist concentration increases. In this type of assay, a concentration of radioligand is used in every assay tube. The ligand is used at a low concentration, usually at or below its Kd value, competition curves may also be computer-fitted to a logistic function as described under direct fit. In this situation the IC50 is the concentration of competing ligand which displaces 50% of the binding of the radioligand. The IC50 value is converted to an absolute inhibition constant Ki using the Cheng-Prusoff equation formulated by Yung-Chi Cheng, IC50 is not a direct indicator of affinity although the two can be related at least for competitive agonists and antagonists by the Cheng-Prusoff equation. Whereas the IC50 value for a compound may vary between experiments depending on conditions, the Ki is an absolute value. Ki is the constant for a drug, the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no ligand were present. The Cheng-Prusoff equation produces good estimates at high agonist concentrations, in these conditions, other analyses have been recommended. Sometimes, IC50 values are converted to the pIC50 scale, PIC50 = − log 10 Note the minus sign, which means that higher values of pIC50 indicate exponentially greater potency. PIC50 is usually given in terms of molar concentration, therefore, to obtain a pIC50, an IC50 should be specified in units of M. When IC50 is expressed in μM or nM, it will need to be converted to M before conversion to pIC50, the IC50 terminology is also used for some behavioral measures in vivo, such as a two bottle fluid consumption test
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Stereoisomerism
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Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms, but differ in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, by definition, molecules that are stereoisomers of each other represent the same structural isomer. Enantiomers, also known as optical isomers, are two stereoisomers that are related to other by a reflection, They are mirror images of each other that are non-superimposable. Human hands are an analog of stereoisomerism. Every stereogenic center in one has the configuration in the other. As a result, different enantiomers of a compound may have different biological effects. Pure enantiomers also exhibit the phenomenon of optical activity and can be separated only with the use of a chiral agent, in nature, only one enantiomer of most chiral biological compounds, such as amino acids, is present. Diastereomers are stereoisomers not related through a reflection operation and they are not mirror images of each other. These include meso compounds, cis–trans isomers, and non-enantiomeric optical isomers, diastereomers seldom have the same physical properties. In the example shown below, the form of tartaric acid forms a diastereomeric pair with both levo and dextro tartaric acids, which form an enantiomeric pair. Please refer to Chirality for more regarding the D- and L- labels. Stereoisomerism about double bonds arises because rotation about the bond is restricted. The simplest examples of cis-trans isomerism are the 1, 2-disubstituted ethenes, molecule I is cis-1, 2-dichloroethene and molecule II is trans-1, 2-dichloroethene. Due to occasional ambiguity, IUPAC adopted a rigorous system wherein the substituents at each end of the double bond are assigned priority based on their atomic number. If the high-priority substituents are on the side of the bond. If they are on sides, it is E. Since chlorine has an atomic number than hydrogen, it is the highest-priority group. Using this notation to name the above pictured molecules, molecule I is -1, 2-dichloroethene and molecule II is -1 and it is not the case that Z and cis or E and trans are always interchangeable
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. PMID 16433932.
