1.
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
2.
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
3.
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
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.
Drug
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A drug is any substance that, when inhaled, injected, smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue, causes a physiological change in the body. In pharmacology, a drug, also called a medication or medicine, is a chemical substance used to treat, cure, prevent. Traditionally drugs were obtained through extraction from plants, but more recently also by organic synthesis. Pharmaceutical drugs may be used for a duration, or on a regular basis for chronic disorders. Another major classification system is the Biopharmaceutics Classification System and this classifies drugs according to their solubility and permeability or absorption properties. Psychoactive drugs are chemical substances that affect the function of the nervous system, altering perception. They include alcohol, a depressant, and the nicotine and caffeine. These three are the most widely consumed psychoactive drugs worldwide and are also considered recreational drugs since they are used for rather than medicinal purposes. Other recreational drugs include hallucinogens, opiates and amphetamines and some of these are used in spiritual or religious settings. Some drugs can cause addiction and all drugs can have side effects, excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition. The transitive verb to drug arose later and invokes the psychoactive rather than properties of a substance. A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition, the use may also be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies and these medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country, medications are typically produced by pharmaceutical companies and are often patented to give the developer exclusive rights to produce them. Those that are not patented are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder, pharmaceutical drugs are usually categorised into drug classes. A group of drugs will share a chemical structure, or have the same mechanism of action. Another major classification system is the Biopharmaceutics Classification System and this groups drugs according to their solubility and permeability or absorption properties
9.
Substituted amphetamine
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The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Some of amphetamines substituted derivatives occur in nature, for example in the leaves of Ephedra and these have been used since antiquity for their pharmacological effects. Amphetamine was first produced at the end of the 19th century, by the 1930s, amphetamine and some of its derivative compounds found use as decongestants in the symptomatic treatment of colds and also occasionally as psychoactive agents. Their effects on the nervous system are diverse, but can be summarized by three overlapping types of activity, psychoanaleptic, hallucinogenic and empathogenic. Various substituted amphetamines may cause these actions either separately or in combination, amphetamines are a subgroup of the substituted phenethylamine class of compounds. Substitution of hydrogen results in a large class of compounds. Natives of Yemen and Ethiopia have a tradition of chewing khat leaves to achieve a stimulating effect. The active substances of khat are cathinone and, to a lesser extent, amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu, although its pharmacological effects remained unknown until the 1930s. MDMA was produced in 1912 as an intermediate product, however, this synthesis also went largely unnoticed. In the 1920s, both methamphetamine and the dextrorotatory optical isomer of amphetamine, dextroamphetamine, were synthesized and this synthesis was a by-product of a search for ephedrine, a bronchodilator used to treat asthma extracted exclusively from natural sources. Over-the-counter use of substituted amphetamines was initiated in the early 1930s by the pharmaceutical company Smith, Kline & French, as a medicine for colds and nasal congestion. Subsequently, amphetamine was used in the treatment of narcolepsy, obesity, hay fever, orthostatic hypotension, epilepsy, Parkinsons disease, alcoholism, the reinforcing effects of substituted amphetamines were quickly discovered, and the misuse of substituted amphetamines had been noted as far back as 1936. During World War II, amphetamines were used by the German military to keep their tank crews awake for long periods and it was noticed that extended rest was required after such artificially induced activity. The widespread use of substituted amphetamines began in postwar Japan and quickly spread to other countries, modified designer amphetamines gained popularity since the 1960s, such as MDA and PMA. In 1970, the United States adopted the Controlled Substances Act that limited non-medical use of substituted amphetamines, street use of PMA was noted in 1972. MDMA emerged as a substitute to MDA in the early 1970s, american chemist Alexander Shulgin first synthesized the drug in 1976 and through him the drug was briefly introduced into psychotherapy. Recreational use grew and in 1985 MDMA was banned by the US authorities in an emergency scheduling initiated by the Drug Enforcement Administration, since the mid-1990s, MDMA has become a popular entactogenic drug among the youth and quite often non-MDMA substances were sold as ecstasy. Ongoing trials are investigating its efficacy as an adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder
10.
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
11.
Fenfluramine
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Fenfluramine, also known as 3-trifluoromethyl-N-ethylamphetamine, is an anorectic that is no longer marketed. In combination with phentermine, it was part of the anti-obesity medication Fen-phen, Fenfluramine was introduced on the U. S. market in 1973 and withdrawn in 1997. It is the mixture of two enantiomers, dexfenfluramine and levofenfluramine. The drug increases the level of serotonin, a neurotransmitter that regulates mood, appetite, Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function. The result is a feeling of fullness and reduced appetite, the drug was withdrawn from the U. S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis. It was subsequently withdrawn from markets around the world. It was banned in India in 1998, the distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent inhibitor of the re-uptake of 5-HT into nerve terminals, Fenfluramine and its active metabolite norfenfluramine affect the 5-HT2B receptors which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT2B receptors, according to a study of 5743 former users conducted by a plaintiffs expert cardiologist, damage to the heart valve continued long after stopping the medication. Of the users tested,20 percent of women, and 12 percent of men were affected, for all ex-users, there was a sevenfold increase of chances of needing surgery for faulty heart valves caused by the drug. There have been reports associating fenfluramine with depression, psychosis, exacerbation of pre-existing psychosis and these effects may be mediated by serotonergic neurotoxicity/depletion of serotonin with chronic administration and/or activation 5-HT2A receptors. In overdose, fenfluramine can result in serotonin syndrome and death, unlike various other amphetamine derivatives, fenfluramine is reported to be dysphoric, unpleasantly lethargic, and non-addictive. At high doses, fenfluramine induces a state resembling that produced by lysergic acid diethylamide. Prepn, L. G. Beregi et al, prepn of optical isomers, eidem, US3198834. Benfluorex Tiflorex Welch, J. T. Lim, D. S, the Synthesis and Biological Activity of Pentafluorosulfanyl Analogs of Fluoxetine, Fenfluramine, and Norfenfluramine. RxList. com - Fenfluramine Inchem. org - Fenfluramine circ. ahajournals. org
12.
5-HT2B receptor
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5-Hydroxytryptamine receptor 2B also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin, the 5-HT2 receptors mediate many of the central and peripheral physiologic functions of serotonin. The 5-HT2B receptor stimulation can also lead to proliferation of cardiac valves fibroblasts. 5-HT2B receptors have also strongly implicated in drug-induced valvular heart disease. In this context, it is considered to be an antitarget. The structure of the 5-HT2B receptor was recently solved in complex with the valvulopathogenic drug ergotamine, as of 2009, few highly selective 5-HT2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT2C binding. Selective BW-723C86, fair functional subtype selectivity, almost full agonist, MDMA MDA MEM Pergolide Cabergoline Norfenfluramine Chlorphentermine Aminorex mCPP Bromo-dragonfly DMT 5-MeO-DMT LSD-25 - About equal affinity for human cloned 5-HT2B and 5-HT2A receptors. Psilocin Agomelatine - primarily a melatonin Mt1/Mt2 receptor agonist, with a less potent antagonism of 5-HT2B, more recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease. Research claims serotonin 5-HT2B receptors have effect on liver regeneration, IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology, human HTR2B genome location and HTR2B gene details page in the UCSC Genome Browser. This article incorporates text from the United States National Library of Medicine, which is in the public domain
13.
Heart valve
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A heart valve normally allows blood to flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart, a heart valve opens or closes incumbent on differential blood pressure on each side. The four main valves in the heart are, The two atrioventricular valves, the valve, and the tricuspid valve, which are between the upper chambers and the lower chambers. The two semilunar valves, the valve and the pulmonary valve, which are in the arteries leaving the heart. The mitral valve and the valve are in the left heart, the tricuspid valve. There are also the coronary sinus and the inferior vena cava valves, the heart valves and the chambers are lined with endocardium. Heart valves separate the atria from the ventricles, or the ventricles from a blood vessel, heart valves are situated around the fibrous rings of the cardiac skeleton. The valves incorporate leaflets or cusps, which are pushed open to allow blood flow, the mitral valve has two cusps, whereas the others have three. There are nodules at the tips of the cusps that make the seal tighter, the pulmonary valve has left, right, and anterior cusps. The aortic valve has left, right, and posterior cusps, the tricuspid valve has anterior, posterior, and septal cusps, and the mitral valve has just anterior and posterior cusps. These are the mitral and tricuspid valves, which are situated between the atria and the ventricles and prevent backflow from the ventricles into the atria during systole and they are anchored to the walls of the ventricles by chordae tendineae, which prevent the valves from inverting. The chordae tendineae are attached to muscles that cause tension to better hold the valve. Together, the muscles and the chordae tendineae are known as the subvalvular apparatus. The function of the apparatus is to keep the valves from prolapsing into the atria when they close. The subvalvular apparatus has no effect on the opening and closure of the valves, however, the peculiar insertion of chords on the leaflet free margin, however, provides systolic stress sharing between chords according to their different thickness. The closure of the AV valves is heard as lub, the first heart sound, the closure of the SL valves is heard as dub, the second heart sound. The mitral valve is called the bicuspid valve because it contains two leaflets or cusps. The mitral valve gets its name from the resemblance to a bishops mitre and it is on the left side of the heart and allows the blood to flow from the left atrium into the left ventricle
14.
Chemical synapse
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Chemical synapses are biological junctions through which neurons signals can be exchanged to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the nervous system. They are crucial to the computations that underlie perception and thought. They allow the system to connect to and control other systems of the body. At a chemical synapse, one neuron releases neurotransmitter molecules into a space that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis and these molecules then bind to receptors on the postsynaptic cells side of the synaptic cleft. The adult human brain is estimated to contain from 1014 to 5 ×1014 synapses, every cubic millimeter of cerebral cortex contains roughly a billion of them. The word synapse comes from synaptein, which Sir Charles Scott Sherrington and colleagues coined from the Greek syn-, chemical synapses are not the only type of biological synapse, electrical and immunological synapses also exist. Without a qualifier, however, synapse commonly means chemical synapse, synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are types that make far fewer. Most synapses connect axons to dendrites, but there are other types of connections, including axon-to-cell-body, axon-to-axon. Chemical synapses pass information directionally from a cell to a postsynaptic cell and are therefore asymmetric in structure. Synaptic vesicles are docked at the plasma membrane at regions called active zones. Immediately opposite is a region of the cell containing neurotransmitter receptors. Immediately behind the postsynaptic membrane is a complex of interlinked proteins called the postsynaptic density. Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors, the receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines. Synapses may be described as symmetric or asymmetric, when examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain a prominent postsynaptic density, the synaptic cleft is a gap between the pre- and postsynaptic cells that is about 20 nm wide
15.
5-HT1B receptor
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5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype, 5-HT1B receptors are widely distributed throughout the CNS with the highest concentrations found in the frontal cortex, basal ganglia, striatum, and the hippocampus. The function of the 5-HT1B receptor differs depending upon its location, in the frontal cortex, it is believed to act as a postsynaptic receptor inhibiting the release of dopamine. In the hippocampus, a recent study has demonstrated that activation of postsynaptic 5-HT1B heteroreceptors produces a facilitation in excitatory synaptic transmission which is altered in depression. When the expression of 5-HT1B in human cortex was traced throughout life, significant changes during adolescence were observed, outside the brain, 5-HT1B receptor activation also has vascular effects, such as pulmonary vasoconstriction. Furthermore, blocking 5-HT1B receptor signalling increases the number of osteoblasts, bone mass, knockout mice lacking the 5-HT1B gene have shown an increase in aggression and a higher preference for alcohol. Under basal conditions, knockout mice present with a normal phenotype, however, after undergoing chronic unpredictable stress treatment to induce a depression-like phenotype these animals do not benefit from administration of selective serotonin reuptake inhibitor. A genetic variant in the region, A-161T, has been examined with respect to personality traits. IUPHAR Database of Receptors and Ion Channels, international Union of Basic and Clinical Pharmacology. Human HTR1B genome location and HTR1B gene details page in the UCSC Genome Browser and this article incorporates text from the United States National Library of Medicine, which is in the public domain
16.
5-HT2C receptor
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The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin. It is a G protein-coupled receptor that is coupled to Gq/G11, HTR2C denotes the human gene encoding for the receptor, that in humans is located at the X chromosome. As males have one copy of the gene and in one of the two copies of the gene is repressed, polymorphisms at this receptor can affect the two sexes to differing extent. At the cell surface the receptor exists as a homodimer, 5-HT2C receptors are widely distributed across the periphery and brain in humans. The 5-HT2C receptor is one of the binding sites for serotonin. Activation of this receptor by serotonin inhibits dopamine and norepinephrine release in areas of the brain. 5-HT2C receptors are claimed to significantly regulate mood, anxiety, feeding, 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others. Research indicates that some victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT2C antagonist, is an effective antidepressant, antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Many atypical antipsychotics block 5-HT2C receptors, but their use is limited by multiple undesirable actions on various neurotransmitters and receptors. Fluoxetine acts as a direct 5-HT2C antagonist in addition to inhibiting serotonin reuptake, however, an overactivity of 5-HT2C receptors may contribute to depressive and anxiety symptoms in a certain population of patients. Activation of 5-HT2C by serotonin is responsible for many of the side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine. Some of the anxiety caused by SSRIs is due to excessive signalling at 5-HT2C. Over a period of 1–2 weeks, the receptor begins to downregulate, along with the downregulation of 5-HT2A, 5-HT1A and this downregulation parallels the onset of the clinical benefits of SSRIs. 5-HT2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy, thus, 5-HT2C receptors do not require binding by a ligand in order to exhibit influence on neurotransmission. Inverse agonists may be required to fully extinguish 5-HT2C constitutive activity, 5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs, including caffeine, nicotine, amphetamine, morphine, cocaine, and others. 5-HT2C antagonism increases dopamine release in response to reinforcing drugs, feeding, social interaction, and sexual activity all release dopamine subject to inhibition of 5-HT2C. Increased 5-HT2C expression reduces dopamine release in both the presence and absence of stimuli, conditions that increase cytokine levels in the human body may have potential to raise 5-HT2C gene expression in the brain
17.
Serotonin releasing agent
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A serotonin releasing agent is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, a closely related type of drug is a serotonin reuptake inhibitor. Amphetamines like MDMA, MDEA, MDA, and MBDB, among other relatives, are recreational drugs termed entactogens and they act as serotonin-norepinephrine-dopamine releasing agents and also agonize serotonin receptors such as those in the 5-HT2 subfamily. Fenfluramine, chlorphentermine, and aminorex, which are also amphetamines and relatives, were used as appetite suppressants but were discontinued due to concerns of cardiac valvulopathy. This side effect has been attributed to their action of potent agonism of the 5-HT2B receptor. The designer drug 4-methylaminorex, which is an SNDRA and 5-HT2B agonist, has reported to cause this effect as well. Many tryptamines, such as DMT, αMT, 5MeO-NMT, NMT, NETP, Dimethyl-Serotonin and these drugs are serotonergic psychedelics, which is a consequence of their ability to activate the 5-HT2A receptor. αET and αMT, also tryptamines, are SNDRAs and non-selective serotonin receptor agonists that were used as antidepressants. They have since discontinued and are now encountered solely as recreational drugs. Tramadol, in addition to its actions as an opioid and norepinephrine reuptake inhibitor, is an SRA and is used as an analgesic and it is also under investigation as an antidepressant. Indeloxazine is an SRA and norepinephrine reuptake inhibitor that was used as an antidepressant, nootropic
18.
5-HT receptor
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They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the serotonin, which acts as their natural ligand. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Serotonin receptors are found in almost all animals and humans and are known to regulate longevity and behavioral aging in the primitive nematode. In 2014 a novel 5-HT receptor was described that was isolated from the white butterfly, Pieris rapae. It shares relatively low similarity to the known 5-HT receptor classes and does not occur in mammals, the 7 general serotonin receptor classes include a total of 14 known serotonin receptors. Very nonselective agonists of 5-HT receptor subtypes include ergotamine, which activates 5-HT1A, 5-HT1D, 5-HT1B, D2, LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist. Serotonin Receptors at the US National Library of Medicine Medical Subject Headings 5-Hydroxytryptamine Receptors, IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology, activation of G protein-coupled receptors entails cysteine modulation of agonist binding. Paterson LM, Kornum BR, Nutt DJ, Pike VW, 5-HT radioligands for human brain imaging with PET and SPECT
19.
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
20.
Side effect
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Occasionally, drugs are prescribed or procedures performed specifically for their side effects, in that case, said side effect ceases to be a side effect, and is now an intended effect. For instance, X-rays were historically used as an imaging technique, buprenorphine has been shown experimentally to be effective against severe, refractory depression. Bupropion, an anti-depressant, is used as a smoking cessation aid, this indication was later approved. In Ontario, Canada, smoking cessation drugs are not covered by provincial drug plans, elsewhere, Zyban is priced higher than Wellbutrin, therefore, some physicians prescribe Wellbutrin for both indications. Dexamethasone and Betamethasone in premature labor, to enhance pulmonary maturation of the fetus, doxepin has been used to treat angiodema and severe allergic reactions due to its strong antihistamine properties. Hydroxyzine, an antihistamine, is used as an anxiolytic. Magnesium sulfate in obstetrics for premature labor and preeclampsia, methotrexate, approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy. The SSRI medication sertraline is approved as an antidepressant but delays conjugal climax in men, sildenafil was originally intended for pulmonary hypertension, subsequently, it was discovered that it also produces erections, for which it was later marketed. Terazosin, an α1-adrenergic antagonist approved to treat benign prostatic hyperplasia, echinacea – more than 20 different types of reactions have been reported, including asthma attacks, loss of pregnancy, hives, swelling, aching muscles and gastrointestinal upsets. Feverfew – pregnant women should avoid using this herb, as it can trigger uterine contractions, in animal experiments, the use of feverfew was found to trigger spontaneous abortions. Asteraceae plants – which include feverfew, echinacea, dandelion and chamomile, side effects include allergic dermatitis and hay fever
21.
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
22.
Serotonin
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Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is found in the gastrointestinal tract, blood platelets. It is popularly thought to be a contributor to feelings of well-being, approximately 90% of the human bodys total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions and these include the regulation of mood, appetite, and sleep. Serotonin also has some functions, including memory and learning. Modulation of serotonin at synapses is thought to be an action of several classes of pharmacological antidepressants. Serotonin secreted from the cells eventually finds its way out of tissues into the blood. There, it is taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver, metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the acetic acid derivative. The latter is then excreted by the kidneys, in addition to animals, serotonin is found in fungi and plants. Serotonins presence in insect venoms and plant spines serves to cause pain, Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds, Serotonin is a neurotransmitter and is found in all bilateral animals, where it mediates gut movements and the animals perceptions of resource availability. In less complex animals, such as invertebrates, resources simply mean food availability. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance, in response to the perceived abundance or scarcity of resources, an animals growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal, except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors that activate an intracellular second messenger cascade. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse and this is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron
23.
Dopamine receptor
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Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system. The neurotransmitter dopamine is the endogenous ligand for dopamine receptors. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders, thus, dopamine receptors are common neurologic drug targets, antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors. The existence of multiple types of receptors for dopamine was first proposed in 1976, there are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of the D1-like family of receptors, whereas the D2, D3. There is also evidence that suggests the existence of possible D6 and D7 dopamine receptors. At a global level, D1 receptors have widespread expression throughout the brain, furthermore, D1-2 receptor subtypes are found at 10-100 times the levels of the D3-5 subtypes. The D1-like family receptors are coupled to the G protein Gsα, D1 is also coupled to Golf. Gsα subsequently activates adenylyl cyclase, increasing the concentration of the second messenger cyclic adenosine monophosphate. D1 is encoded by the Dopamine receptor D1 gene, D5 is encoded by the Dopamine receptor D5 gene. The D2-like family receptors are coupled to the G protein Giα, D2 is encoded by the Dopamine receptor D2 gene, of which there are two forms, D2Sh and D2Lh, The D2Sh form is pre-synaptically situated, having modulatory functions. The D2Lh form may function as a classical post-synaptic receptor, i. e. transmit information unless blocked by a receptor antagonist or a partial agonist. D3 is encoded by the Dopamine receptor D3 gene, maximum expression of dopamine D3 receptors is noted in the islands of Calleja and nucleus accumbens. D4 is encoded by the Dopamine receptor D4 gene, the D4 receptor gene displays polymorphisms that differ in a variable number tandem repeat present within the coding sequence of exon 3. Some of these alleles are associated with incidence of certain disorders. For example, the D4.7 alleles have an association with attention-deficit hyperactivity disorder. Dopamine receptors have shown to heterodimerize with a number of other G protein-coupled receptors. The D2 class of receptors produce the effect, as they are Gαi coupled receptors
24.
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
25.
Atypical antipsychotic
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The atypical antipsychotics are a group of antipsychotic drugs used to treat psychiatric conditions. Some atypical antipsychotics have received approval for schizophrenia, bipolar disorder, autism. Both generations of medication tend to block receptors in the brains dopamine pathways, however, only a few of the atypicals have been demonstrated to be superior to lesser-used, low-potency first-generation antipsychotics in this regard. It has been argued that a more nuanced view in which the needs of patients are matched to the properties of individual drugs is more appropriate. Significant weight gain may also occur, critics have argued that the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction. Atypical antipsychotics are typically used to treat schizophrenia or bipolar disorder and they are also frequently used to treat agitation associated with dementia, anxiety disorder, Autism Spectrum Disorder, and obsessive-compulsive disorder. In dementia, they should only be considered after other treatments have failed, the first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of psychosis in about 8–15 days. Antipsychotics, however, fail to improve the negative symptoms. The choice of which antipsychotic to use for a patient is based on benefits, risks. It is debatable whether, as a class, typical or atypical antipsychotics are better, both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. There is a response in 40–50% of patients, a partial response in 30–40%. Clozapine is a treatment for those who respond poorly to other drugs. The utility of grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of drugs to the needs of specific patients is preferable. In 2005 the US government body NIMH published the results of a major independent multi-site and this study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1,493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate, a phase 2 part of this CATIE study roughly replicated these findings. Compliance has not been shown to be different between the two types, in bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers such as lithium and valproate. In milder cases of mania or mixed episodes, mood stabilizer monotherapy may be attempted first, SGAs are also used to treat other aspects of the disorder as adjuncts or as a monotherapy, depending on the drug
26.
Weight gain
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Weight gain is an increase in body weight. This can involve an increase in mass, fat deposits. Weight gain can be a symptom of a medical condition. If enough weight is gained due to increased body fat deposits, one may become overweight or obese, the Body Mass Index measures body weight in proportion to the square of height and defines optimal, insufficient, and excessive weight based on the ratio. Weight gain has a latency period, typical latency periods vary from three days to two weeks after ingestion. Having excess adipose tissue is a condition, especially where food supplies are plentiful. As much as 64% of the United States adult population is considered overweight or obese. A commonly asserted rule for weight gain or loss is based on the assumption that one pound of human fat tissue contains about 3,500 kilocalories, thus, eating 500 fewer calories than one needs per day should result in a loss of about a pound per week. Similarly, for every 3500 calories consumed above the amount one needs and he notes that previous research suggested that a pound of human adipose tissue is 87% fat, which equals 395 grams of fat. He further assumes that animal fat contains 9.5 calories per gram, thus one pound of human fat tissue should contain 3750 calories. He concludes that a 3500 calorie excess or deficit for a person meeting his assumptions, would lead to the gain or loss, respectively, of one pound of body weight. He notes that if the assumptions he makes are not met, in any case, Wishnofsky did not take into account numerous aspects of human physiology and biochemistry which refute this simple equivalence. Unfortunately, the claim has achieved the status of a rule of thumb and is repeated in numerous sources, used for planning by dietitians. In regard to adipose tissue increases, a person gains weight by increasing food consumption, becoming physically inactive. When energy intake exceeds energy expenditure, the body can store the energy as fat. However, the physiology of weight gain and loss is complex involving numerous hormones, body systems, the human microbiota facilitates fermentation of indigestible carbohydrates to short-chain fatty acids, SCFAs, contributing to weight gain. A change in the proportion of Bacteroidetes and Firmicutes may determine host’s risk of obesity, lack of sufficient sleep has been suggested as a cause for weight gain or the difficulty in maintaining a healthy weight. As a result, sleep deprivation over time may contribute to increased caloric intake and decreased self-control over food cravings, weight gain is a common side-effect of certain psychiatric medications
27.
Norepinephrine reuptake inhibitor
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This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase in adrenergic neurotransmission. NRIs are commonly used in the treatment of conditions like ADHD and narcolepsy due to their psychostimulant effects and they are also frequently used as antidepressants for the treatment of major depressive disorder, anxiety and panic disorder. A meta analysis published in BMJ in 2011 concluded that the norepinephrine reuptake inhibitor reboxetine is indistinguishable from placebo in the treatment of depression. A second review by the European Medicines Agency concluded that reboxetine was significantly more effective than placebo, a closely related type of drug is a norepinephrine releasing agent. Protriptyline, Nortriptyline, and Desipramine are examples of these, note, Only NRIs selective for the NET greater than the other two monoamine transporters are listed here. For a list of NRIs that act at multiple MATs, see the other monoamine reuptake inhibitor such as NDRI, SNRI
28.
Norepinephrine
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Norepinephrine, also called noradrenaline or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone and neurotransmitter. Norepinephrine is also the international nonproprietary name given to the drug, regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic. In the brain, norepinephrine is produced in closely packed brain cell neurons or nuclei that are small yet exert powerful effects on brain areas. The most important of these nuclei is the locus coeruleus, located in the pons, regardless of how and where it is released, norepinephrine acts on target cells by binding to and activating noradrenergic receptors located on the cell surface. The general function of norepinephrine is to mobilize the brain and body for action, norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, a variety of medically important drugs work by altering the actions of norepinephrine systems. Norepinephrine itself is used as an injectable drug for the treatment of critically low blood pressure. Beta blockers, which some of the effects of norepinephrine, are frequently used to treat glaucoma, migraine. Alpha blockers, which counter a different set of effects, are used to treat several cardiovascular. Alpha-2 agonists often have an effect, and are commonly used as anesthesia-enhancers in surgery. Many important psychiatric drugs exert strong effects on systems in the brain. Norepinephrine is a catecholamine and a phenethylamine and its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word normal, norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. These amino acids are found in nearly every protein and, as such, are provided by ingestion of protein-containing food, phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the tyrosine hydroxylase, with tetrahydrobiopterin, O2. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, dopamine is then converted into norepinephrine by the enzyme dopamine β-monooxygenase, with O2 and ascorbic acid as cofactors. Norepinephrine itself can further be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as cofactor, in mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the monoamine oxidase or COMT
29.
Dopamine
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Dopamine is an organic chemical of the catecholamine and phenethylamine families that plays several important roles in the brain and body. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, dopamine is also synthesized in plants and most multicellular animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to nerve cells. The brain includes several distinct dopamine pathways, one of plays a major role in reward-motivated behavior. Most types of rewards increase the level of dopamine in the brain, other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a system which is neuromodulatory. Outside the central system, dopamine functions primarily as a local chemical messenger. With the exception of the vessels, dopamine in each of these peripheral systems is synthesized locally. Several important diseases of the system are associated with dysfunctions of the dopamine system. Parkinsons disease, a condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Its metabolic precursor L-DOPA can be manufactured, and in its pure form marketed as Levodopa is the most widely used treatment for the condition. There is evidence that schizophrenia involves altered levels of dopamine activity, similar dopamine antagonist drugs are also some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder are associated with decreased dopamine activity, dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. A dopamine molecule consists of a structure with one amine group attached via an ethyl chain. As such, dopamine is the simplest possible catecholamine, a family that includes the neurotransmitters norepinephrine and epinephrine. The presence of a ring with this amine attachment makes it a substituted phenethylamine. Like most amines, dopamine is an organic base, as a base, it is generally protonated in acidic environments. The protonated form is highly water-soluble and relatively stable, but can become oxidized if exposed to oxygen or other oxidants, in basic environments, dopamine is not protonated