1.
Norcocaine
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Not to be confused with Nocaine Norcocaine is a minor metabolite of cocaine. It is the only confirmed pharmacologically active metabolite of cocaine, although salicylmethylecgonine is also speculated to be an active metabolite, the local anesthetic potential of norcocaine has been shown to be higher than that of cocaine, however cocaine continues to be more widely used. Norcocaine used for research purposes is typically synthesized from cocaine, several methods for the synthesis have been described. The legal status of norcocaine is somewhat ambiguous, the US DEA does not list norcocaine as a controlled substance. However, some suppliers of norcocaine, like Sigma-Aldrich, consider the drug to be a Schedule II drug for the purpose of their own sales, the LD50 of norcocaine has been studied in mice. When administered by the route the LD50 in mice was 40 mg/kg. Some researchers have suggested that hair drug testing for use should include testing for metabolites like norcocaine. The basis for this suggestion is the potential for contamination of hair during testing. There is considerable debate about whether current means of washing hair samples are sufficient for removing external contamination, some researchers state the methods are sufficient, while others state the residual contamination may result in a false positive test. Metabolites of cocaine, like norcocaine, in addition to cocaine, authors have stated that the metabolites should be present in any samples declared positive. Issues arise because the metabolites are present in low concentrations. If the metabolites are present, it is possible for them to be from other contamination
2.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service
3.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses
4.
Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH
5.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D
6.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES
7.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure
8.
Stimulant
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Stimulants is an overarching term that covers many drugs including those that increase activity of the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Due to their rendering a characteristic up feeling, stimulants are also referred to as uppers. Depressants or downers, which decrease mental and/or physical function, are in stark contrast to stimulants and are considered to be the functionally opposite drug class, Stimulants are widely used throughout the world as prescription medicines as well as without a prescription as performance-enhancing or recreational drugs. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine, methylphenidate and it is estimated that the percent of the population that has abused amphetamines, cocaine and MDMA combined is between. 8% and 2. 1%. Stimulants in therapeutic doses, such as given to patients with ADHD, increases ability to focus, vigor, sociability, libido. However, in higher doses stimulants may actually decrease the ability to focus, in higher doses stimulants may also produce euphoria, vigor, and decrease need for sleep. Many, but not all, stimulants have ergogenic effects, Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while drugs such as cocaine and methamphetamine have the opposite effect. In some cases psychiatric phenomenon may emerge such as stimulant psychosis, paranoia, acute toxicity has been reportedly associated with a homicide, paranoia, aggressive behavior, motor dysfunction, and punding. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia, most drugs classified as stimulants are sympathomimetics, that is they stimulate the sympathetic branch of the autonomic nervous system. This leads to such as mydriasis, increased heart rate, blood pressure, respiratory rate. When these changes become pathological, they are called arrhythmia, hypertension, and hyperthermia, however given the complexity of the mechanisms that underly these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal. Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, a review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer term studies. A review of a long period of prescription stimulate use in those with ADHD found that cardiovascular side effects were limited to transient increases in blood pressure only. Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, Abuse of prescription stimulants or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of disease, stroke. Cocaine may also increase risk for disease, as well as damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, Drugs used to treat sleep disorders such as excessive daytime sleepiness are called eugeroics, and include notable stimulants such as modafinil
9.
Pethidine
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Pethidine, also known as meperidine and Demerol, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1939 as an anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben. Pethidine is indicated for the treatment of moderate to severe pain, for much of the 20th century, pethidine was the opioid of choice for many physicians, in 1975, 60% of doctors prescribed it for acute pain and 22% for chronic severe pain. The norpethidine metabolite was found to have effects, so pethidine could, unlike most opioids. Pethidine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN9230 with a 6250 kilo aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride and 0.84 for the hydrobromide. The A, B, and C intermediates in production of pethidine are also controlled 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. It is still used in the United Kingdom and New Zealand. Pethidine is the preferred painkiller for diverticulitis, because it decreases intestinal intraluminal pressure, the adverse effects of pethidine administration are primarily those of the opioids as a class, nausea, vomiting, sedation, dizziness, diaphoresis, urinary retention, and constipation. Unlike other opioids, it does not cause miosis because of its anticholinergic properties, overdose can cause muscle flaccidity, respiratory depression, obtundation, cold and clammy skin, hypotension, and coma. A narcotic antagonist such as naloxone is indicated to reverse respiratory depression, serotonin syndrome has occurred in patients receiving concurrent antidepressant therapy with selective serotonin reuptake inhibitors or monoamine oxidase inhibitors. Convulsive seizures sometimes observed in patients receiving parenteral pethidine on a chronic basis have been attributed to accumumulation in plasma of the metabolite norpethidine, fatalities have occurred following either oral or intravenous pethidine overdose. Pethidine has serious interactions that can be dangerous with monoamine oxidase inhibitors, such patients may suffer agitation, delirium, headache, convulsions, and/or hyperthermia. Fatal interactions have been reported including the death of Libby Zion and it is thought to be caused by an increase in cerebral serotonin concentrations. It is probable that pethidine can also interact with a number of medications, including muscle relaxants, some antidepressants, benzodiazepines. Like morphine, pethidine exerts its effects by acting as an agonist at the μ-opioid receptor. Pethidine is often employed in the treatment of postanesthetic shivering, the pharmacologic mechanism of this antishivering effect is not fully understood, but it may involve the stimulation of κ-opioid receptors. Pethidine has structural similarities to atropine and other alkaloids and may have some of their effects
10.
RTI-31
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-2β-Carbomethoxy-3β-tropane is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material, according to the article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN35428 was 6 x weaker than RTI-31, whereas RTI-51 was 2.6 x weaker than RTI-31, a further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction, RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary. RTI-336 is actually made using RTI-31 as starting material, RTI-31 is not an entirely selective DRI in that it also has appreciable SERT and NET blocking affinity. RTI-31 can easily be cleaned though, as is done, for instance, the binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT, there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, also it needs to be borne in mind the idea of transporter promiscuity. It may be possible that the NE levels are raised, at least in part, RTI-31 lies somewhere in the middle of the table between troparil on one end and RTI-55 on the other. It is not as selective as RTI-113 for the DAT, but is more selective than Dichloropane is for this transporter, RTI-31 also has some muscarinic acetylcholine agonist activity. Data in Above table from rats brains, more recent work has advocated using cloned human transporters. Reduced ester to alcohol is called RTI-93, rTI-145 is a methyl carbonate of the alcohol. Conversion of ester in RTI-31 to heteroaromatic nuclei also possible, rTI-470 was among the potent DRI known to exist,0. 094nM. Further chemical modification of RTI-31 leads to novel chemical entities, some of them are highly potent and this is because of the compounds increased lipophilicity. The act of changing a drugs duration of action through altering its lipophilicity is commonly observed, if read nocaine, interesting n-propyl group chosen, -CPCA RTI-336 RTI-113
11.
Tropane
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Tropane is a nitrogenous bicyclic organic compound. It is mainly known for a group of derived from it. Tropane alkaloids occur in plants of the families Erythroxylaceae and Solanaceae, the nitrogen bridge is between C-1 and C-5, there are two asymmetric carbons, but tropane is optically inactive due to symmetry. 8-Azabicyclooctane is known as nortropane or nor-tropane, phenyltropane Tropane alkaloid Tropine Tropane Chemistry
12.
Phenyl group
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In organic chemistry, the phenyl group or phenyl ring is a cyclic group of atoms with the formula C6H5. Phenyl groups are related to benzene and can be viewed as a benzene ring, minus a hydrogen. Phenyl groups have six carbon atoms bonded together in a planar ring, five of which are bonded to individual hydrogen atoms. Phenyl groups are commonplace in organic chemistry, although often depicted with alternating double and single bonds, phenyl groups are chemically aromatic and show nearly equal bond lengths between carbon atoms in the ring. Usually, a group is synonymous to C6H5– and is represented by the symbol Ph or, archaically. Benzene is sometimes denoted as PhH, Phenyl groups are generally attached to other atoms or groups. For example, triphenylmethane has three groups attached to the same carbon center. Many or even most phenyl compounds are not described with the term phenyl, for example, the chloro derivative C6H5Cl is normally called chlorobenzene, although it could be called phenyl chloride. For example, O2NC6H4 is nitrophenyl and F5C6 is pentafluorophenyl, monosubstituted phenyl groups are associated with electrophilic aromatic substitution reactions and the products follow the arene substitution pattern. So, a substituted phenyl compound has three isomers, ortho, meta and para. A disubstituted phenyl compound may be, for example,1,3, 5-trisubstituted, or 1,2, higher degrees of substitution, of which the pentafluorophenyl group is an example, exist, and are named according to IUPAC nomenclature. Phenyl compounds are derived from benzene, at least conceptually and often in terms of their production, in terms of its electronic properties, the phenyl group is related to a vinyl group. Phenyl groups tend to resist oxidation and reduction, Phenyl groups have enhanced stability in comparison to equivalent bonding in aliphatic groups. This increased stability is due to the properties of aromatic molecular orbitals. The bond lengths between carbon atoms in a group are approximately 1.4 Å. In 1H-NMR spectroscopy, protons of a group typically have chemical shifts around 7.27 ppm. These chemical shifts are influenced by aromatic ring current and may change depending on substituents, Phenyl groups are usually introduced using reagents that behave as sources of the phenyl anion or the phenyl cation. Representative reagents include phenyllithium and phenylmagnesium bromide, electrophiles attack benzene to give phenyl derivatives, C6H6 + E+ → C6H5E + H+ where E+ = Cl+, NO2+, SO3
13.
Piperidine
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Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a ring containing five methylene bridges. It is a liquid with an odor described as objectionable. The name comes from the genus name Piper, which is the Latin word for pepper, although, piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and alkaloids. Piperidine was first reported in 1850 by the Scottish chemist Thomas Anderson and again, independently, in 1852 by the French chemist Auguste Cahours, both men obtained piperidine by reacting piperine with nitric acid. Piperidine itself has been obtained from black pepper, from Psilocaulon absimile, the piperidine structural motif is present in numerous natural alkaloids. These include piperine, which gives black pepper its spicy taste and this gave the compound its name. Piperidine prefers a chair conformation, similar to cyclohexane, unlike cyclohexane, piperidine has two distinguishable chair conformations, one with the N–H bond in an axial position, and the other in an equatorial position. After much controversy during the 1950s–1970s, the equatorial conformation was found to be stable by 0.72 kcal/mol in the gas phase. In nonpolar solvents, a range between 0.2 and 0.6 kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable. In the case of N-methylpiperidine, the conformation is preferred by 3.16 kcal/mol. Piperidine is a widely used secondary amine and it is widely used to convert ketones to enamines. Enamines derived from piperidine can be used in the Stork enamine alkylation reaction, Piperidine can be converted to the chloramine C5H10NCl with calcium hypochlorite. The resulting chloramine undergoes dehydrohalogenation to afford the cyclic imine, 13C NMR,47.27.2,25.2 1H NMR,2.79,2.19,1.51 Piperidine is used as a solvent and as a base. A significant industrial application of piperidine is for the production of dipiperidinyl dithiuram tetrasulfide, Piperidine and its derivatives are ubiquitous building blocks in the synthesis of pharmaceuticals and fine chemicals. Piperidine is also used as a base for the deprotection of Fmoc-amino acids used in solid-phase peptide synthesis
14.
Cocaine
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Cocaine, also known as coke, is a strong stimulant mostly used as a recreational drug. It is commonly snorted, inhaled, or injected into the veins, mental effects may include loss of contact with reality, an intense feeling of happiness, or agitation. Physical symptoms may include a fast heart rate, sweating, high doses can result in very high blood pressure or body temperature. Effects begin within seconds to minutes of use and last between five and ninety minutes, Cocaine has a small number of accepted medical uses such as numbing and decreasing bleeding during nasal surgery. Cocaine is addictive due to its effect on the pathway in the brain. After a short period of use, there is a risk that dependence will occur. Its use also increases the risk of stroke, myocardial infarction, lung problems in those who smoke it, blood infections, Cocaine sold on the street is commonly mixed with local anesthetics, cornstarch, quinine, or sugar which can result in additional toxicity. Following repeated doses a person may have decreased ability to feel pleasure, Cocaine acts by inhibiting the reuptake of serotonin, norepinephrine, and dopamine. This results in concentrations of these three neurotransmitters in the brain. It can easily cross the barrier and may lead to the breakdown of the barrier. Cocaine is made from the leaves of the plant which are mostly grown in South America. In 2013,419 kilograms were produced legally and it is estimated that the illegal market for cocaine is 100 to 500 billion USD each year. With further processing crack cocaine can be produced from cocaine, after cannabis, cocaine is the most frequently used illegal drug globally. Between 14 and 21 million people use the drug each year, use is highest in North America followed by Europe and South America. Between one and three percent of people in the world have used cocaine at some point in their life. In 2013 cocaine use resulted in 4,300 deaths. The leaves of the plant have been used by Peruvians since ancient times. Cocaine was first isolated from the leaves in 1860, since 1961 the international Single Convention on Narcotic Drugs has required countries to make recreational use of cocaine a crime
15.
Arecoline
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Arecoline is a nicotinic acid-based alkaloid found in the areca nut, the fruit of the areca palm. It is an oily liquid. Arecoline is a base, and its conjugate acid has a pKa ~6.8, arecoline is volatile in steam, miscible with most organic solvents and water, but extractable from water by ether in presence of dissolved salts. Being basic, arecoline forms salts with acids, the salts are crystalline, but usually deliquescent, the hydrochloride, arecoline•HCl, forms needles, m. p.158 °C, the hydrobromide, arecoline•HBr, forms slender prisms, mp. 177-179 °C from hot alcohol, the aurichloride, arecoline•HAuCl4, is an oil, the methiodide forms glancing prisms, mp. In many Asian cultures, the nut is chewed along with betel leaf to obtain a stimulating effect. Arecoline is the active ingredient responsible for the central nervous system effects of the areca nut. Arecoline has been compared to nicotine, however, nicotine acts primarily on the acetylcholine receptor. Arecoline is known to be a partial agonist of muscarinic acetylcholine M1, M2, M3 receptors and M4, lD50,100 mg/kg, administered subcutaneously in mouse. Current science is confident that areca nut chewing is carcinogenic, section 5.5 Evaluation on page 238 of IARC Monograph 85-6 states the following, There is sufficient evidence in humans for the carcinogenicity of betel quid without tobacco. Betel quid without tobacco causes oral cancer, There is sufficient evidence in experimental animals for the carcinogenicity of betel quid without tobacco. There is sufficient evidence in animals for the carcinogenicity of betel quid with tobacco. There is sufficient evidence in animals for the carcinogenicity of areca nut. There is sufficient evidence in animals for the carcinogenicity of areca nut with tobacco. There is limited evidence in animals for the carcinogenicity of arecoline. There is inadequate evidence in animals for the carcinogenicity of arecaidine. Owing to its muscarinic and nicotinic agonist properties, arecoline has shown improvement in the ability of healthy volunteers. Arecoline has also used medicinally as an antihelmintic
16.
Femoxetine
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Femoxetine is a drug related to paroxetine that was being developed as an antidepressant by Danish pharmaceutical company Ferrosan in 1975 before acquisition by Novo Nordisk. It acts as a serotonin reuptake inhibitor. Development was halted to focus attention on paroxetine instead, given femoxetines inability to be administered as a daily pill, both femoxetine and paroxetine were invented in the 1970s by Jorgen Buus-Lassen. Jorgen Buus-Lassens name is on the paper though. After Ferrosans acquisition, femoxetine died from neglect
17.
Chemical substance
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A chemical substance is a form of matter that has constant chemical composition and characteristic properties. It cannot be separated into components by physical methods, i. e. without breaking chemical bonds. Chemical substances can be chemical elements, chemical compounds, ions or alloys, Chemical substances are often called pure to set them apart from mixtures. A common example of a substance is pure water, it has the same properties. Other chemical substances commonly encountered in pure form are diamond, gold, table salt, however, in practice, no substance is entirely pure, and chemical purity is specified according to the intended use of the chemical. Chemical substances exist as solids, liquids, gases, or plasma, Chemical substances may be combined or converted to others by means of chemical reactions. Forms of energy, such as light and heat, are not matter, a chemical substance may well be defined as any material with a definite chemical composition in an introductory general chemistry textbook. According to this definition a chemical substance can either be a chemical element or a pure chemical compound. But, there are exceptions to this definition, a substance can also be defined as a form of matter that has both definite composition and distinct properties. The chemical substance index published by CAS also includes several alloys of uncertain composition, in geology, substances of uniform composition are called minerals, while physical mixtures of several minerals are defined as rocks. Many minerals, however, mutually dissolve into solid solutions, such that a rock is a uniform substance despite being a mixture in stoichiometric terms. Feldspars are an example, anorthoclase is an alkali aluminium silicate. In law, chemical substances may include both pure substances and mixtures with a composition or manufacturing process. For example, the EU regulation REACH defines monoconstituent substances, multiconstituent substances and substances of unknown or variable composition, the latter two consist of multiple chemical substances, however, their identity can be established either by direct chemical analysis or reference to a single manufacturing process. For example, charcoal is a complex, partially polymeric mixture that can be defined by its manufacturing process. Therefore, although the chemical identity is unknown, identification can be made to a sufficient accuracy. The CAS index also includes mixtures, polymers almost always appear as mixtures of molecules of multiple molar masses, each of which could be considered a separate chemical substance. However, the polymer may be defined by a precursor or reaction
18.
Cholinergic
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In general, the word choline refers to the various quaternary ammonium salts containing the N, N, N-trimethylethanolammonium cation. Found in most animal tissues, choline is a component of the neurotransmitter acetylcholine. It prevents fat deposits in the liver and facilitates the movement of fats into the cells, the richest sources of choline are liver, kidney, brain, wheat germ, brewers yeast, and egg yolk. Neurologically, cholinergic is the term referring to acetylcholine. The parasympathetic nervous system, which uses acetylcholine almost exclusively to send its messages, is said to be almost entirely cholinergic, neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholinergic. In addition, the receptor for the sweat glands are also cholinergic. Such mimics are called parasympathomimetic drugs or cholinomimetic drugs, a receptor is cholinergic if it uses acetylcholine as its neurotransmitter. A synapse is cholinergic if it uses acetylcholine as its neurotransmitter, a molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group, the molecule should have an oxygen atom, preferably an ester-like oxygen capable of participating in a hydrogen bond. The hypothesis states that a cause of AD is the reduced synthesis of acetylcholine. Many current drug therapies for AD are centered on the cholinergic hypothesis, studies performed in the 1980s demonstrated significant impairment of cholinergic markers in Alzheimer’s patients. Scopolamine, a drug, was used to block cholinergic activity in young adults. The memory impairments were reversed when treated with physostigmine, a cholinergic agonist, however, reversing memory impairments in AD patients may not be this easy due to permanent changes in brain structure. When young adults perform memory and attention tasks, brain activation patterns are balanced between the frontal and occipital lobes, creating a balance between bottom-up and top-down processing. Normal cognitive aging may affect long term and working memory, though the cholinergic system, adults with AD presenting with dysfunction of the cholinergic system are not able to compensate for long-term and working memory deficits. AD is currently treated by increasing acetylcholine concentration by using acetylcholinesterase inhibitors to inhibit acetylcholinesterase from breaking down acetylcholine, current acetylcholinesterase inhibitors approved in the United States by the FDA to treat Alzheimer’s include donepezil, rivastigmine, and galantamine. These drugs work to increase the levels of acetylcholine and subsequently increase the function of neural cells, however, not all treatments based upon the cholinergic hypothesis have been successful in treating the symptoms or slowing the progression of AD. Therefore, a disruption to the system has been proposed as a consequence of AD rather than a direct cause
19.
Dopamine transporter
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DAT is implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, and alcoholism. The gene that encodes the DAT protein is located on human chromosome 5, consists of 15 coding exons, DAT is an integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. Dopamine underlies several aspects of cognition, including reward, and DAT facilitates regulation of that signal, DAT is a symporter that moves dopamine across the cell membrane by coupling the movement to the energetically-favorable movement of sodium ions moving from high to low concentration into the cell. DAT function requires the binding and co-transport of two Na+ ions and one Cl− ion with the dopamine substrate. The driving force for DAT-mediated dopamine reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase, in the most widely accepted model for monoamine transporter function, sodium ions must bind to the extracellular domain of the transporter before dopamine can bind. Once dopamine binds, the protein undergoes a change, which allows both sodium and dopamine to unbind on the intracellular side of the membrane. Chloride ions are also needed to prevent a buildup of positive charge and these studies have also shown that transport rate and direction is totally dependent on the sodium gradient. Because of the coupling of the membrane potential and the sodium gradient. In addition, the transporter may contribute to dopamine release when the neuron depolarizes, preliminary evidence suggests that the dopamine transporter couples to L-type voltage-gated calcium channels, which are expressed in virtually all dopamine neurons. The initial determination of the topology of DAT was based upon hydrophobic sequence analysis. These methods predicted twelve transmembrane domains with an extracellular loop between the third and fourth TMDs. The exact structure of the transporter was elucidated in 2013 by X-ray crystallography, regional distribution of DAT has been found in areas of the brain with established dopaminergic circuitry including, nigrostriatal, mesolimbic, and mesocortical pathways. The nuclei that make up these pathways have distinct patterns of expression, gene expression patterns in the adult mouse show high expression in the substantia nigra pars compacta. This pattern makes sense for a protein that regulates dopamine levels in the synapse, staining in the striatum and nucleus accumbens of the mesolimbic pathway was dense and heterogeneous. In the striatum, DAT is localized in the membrane of axon terminals. Double immunocytochemistry demonstrated DAT colocalization with two markers of nigrostriatal terminals, tyrosine hydroxylase and D2 dopamine receptors. The latter was thus demonstrated to be an autoreceptor on cells that release dopamine, surprisingly, DAT was not identified within any synaptic active zones. These results suggest that striatal dopamine reuptake may occur outside of synaptic specializations once dopamine diffuses from the synaptic cleft, in the substantia nigra, DAT is localized to axonal and dendritic plasma membranes
20.
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
21.
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
22.
Methylecgonidine
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Methylecgonidine is a chemical intermediate derived from ecgonine or cocaine. Methylecgonidine has been shown to be more harmful to the body than other byproducts of cocaine, for example to the heart. The toxicity is due to a partial agonist effect at M1 and M3 muscarinic receptors, leading to DNA fragmentation, AEME is also used in scientific research for the manufacture of phenyltropane analogues such as troparil, dichloropane, iometopane, and CFT. Methylecgonidine could also theoretically be used to produce cocaine and so may be a substance in some countries. Methylecgonidine can be synthesized non pyrolytically from cocaine via hydrolysis/dehydration followed by esterification with methanol, the scheme by Kline is based on the reaction of 2,4, 6-cycloheptatriene-7-carboxylic acid with methylamine. This is a version of U. S. Patent 2,783,235 by Grundmann and Ottmann, patent 2,783,236 these same authors react their methylecgonidine with two equivalents of PhLi to form a tertiary alcohol by hard addition to the ester and not soft Michael addition. However, the product is one tenth the potency of atropine. The methyl 2,4, 6-cycloheptatriene-1-carboxylate can be made synthetically, davies et al. synthesized -methylecgonidine by a tandem cyclopropanation/Cope rearrangement. Thus, reaction of methyldiazobutenoate with 5 equiv of N-pyrrole in the presence of rhodium hexanoate/hexane gave the -azabicyclic system -8 in 62% yield, the unsubstituted double bond was selectively reduced using Wilkinson catalyst to provide N-protected anhydroecgonine methyl ester. Following deprotection of N8 nitrogen with TBAF and reductive methylation with formaldehyde and sodium cyanoborohydride, -5 was obtained in overall good yield
23.
SNDRI
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It does this by concomitantly inhibiting the serotonin transporter, norepinephrine transporter, and dopamine transporter, respectively. SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder, however, increased side effects and abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts. The SNDRIs are similar to non-selective monoamine oxidase inhibitors such as phenelzine and tranylcypromine in that they increase the action of all three of the major monoamine neurotransmitters. One of the ways in which this is so is that SNDRIs lack the entactogenic, psychedelic, cocaine is a naturally occurring SNDRI with a fast onset and short duration that is widely encountered as a drug of abuse. Although their primary mechanisms of action are as NMDA receptor antagonists, major depressive disorder is the foremost reason supporting the need for development of an SNDRI. According to the World Health Organization, depression is the cause of disability. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs, about 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individuals lifetime. Other symptoms including poor concentration, a disturbance of sleep rhythms, individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature. Although common in the elderly, over the course of the last century, however, depressive states are now frequently identified in adolescents and even children. The ability to work, familial relationships, social integration, the genetic contribution has been estimated as 40-50%. However, combinations of genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression. There remains a need for more efficacious antidepressant agents, although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal. In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy, also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants. Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy, although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of adaptive changes. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to symptoms, including impaired motivation, concentration. DA may promote neurotrophic processes in the hippocampus, as 5-HT. Dense connections exist between monoaminergic neurons, dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus and locus coeruleus, respectively
24.
Monoamine transporter
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Monoamine transporters are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters, MATs are located just outside the synaptic cleft, transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through phosphorylation and posttranslational modification, furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in a large part by their interaction with MATs, by keeping the transporters from mopping up the dopamine. There are several different monoamine transporters located along the plasma membrane, DAT is responsible for the Na +/Cl − -dependent reuptake of extracellular dopamine. DAT can also transport extracellular norepinephrine, DATs can be found in the central nervous system, where they are localized in the substantia nigra and ventral tegmental area. DATs are also found in the nervous system where they are localized in the stomach. Various kinases have been linked to DAT regulation including PKA, PKC, PI-3K, ERK1, ERK2, Akt, CaMKII, CDK5, NET is responsible for the Na +/Cl − -dependent reuptake of extracellular norepinephrine. NET can also reuptake extracellular DA, within the CNS, NET is localized to the dendrites and axons found in both the hippocampus and cortex. Peripherally, NET can be found in sympathetic neurons, the adrenal medulla, the lung, the placenta. Regulation of NET has been linked to MAPKs, insulin, PKC, SERT is responsible for the reuptake of extracellular serotonin in a Na +/Cl − -dependent process. In the CNS, SERT is found localized in the cortex, CA1 and CA3 regions of the hippocampus, as well as the median. In the PNS, SERT is localized to the tract, adrenal glands, placenta, lung. Expression of SERT in platelets is used as a means to reacquire 5-HT from the extracellular environment, regulation of SERT has been linked to acute depletion of intracellular Ca Na 2+, calmodulin inhibition, CaMKII, Src, p38 MAP kinase, PKC, and activation of NOS/cGMP. Monoamine transporters are members of the group of Na +/Cl − -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family, MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH2 and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells, all MATs contain sites for protein kinase phosphorylation by cAMP-dependent protein kinase, protein kinase C and Ca2+/calmodulin-dependent protein kinase. MATs are responsible for the uptake of monoamines by the binding and co-transport of Na +. The ion concentration gradient generated by the plasma membrane Na+/K+ ATPase provides the force for the transporter-mediated monoamine uptake. In the case of NET and SERT one Na+ and one Cl− ion are transported into the cell with one NE or 5-HT respectively, in the case of DAT two Na+ and one Cl− ion are transported along with one DA
25.
Pharmacophore
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A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. A pharmacophore model explains how structurally diverse ligands can bind to a receptor site. Furthermore, pharmacophore models can be used to identify through de novo design or virtual screening novel ligands that bind to the same receptor. Typical pharmacophore features include hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donors, cations and these pharmacophoric points may be located on the ligand itself or may be projected points presumed to be located in the receptor. The features need to match different chemical groups with similar properties, ligand-receptor interactions are typically “polar positive”, “polar negative” or “hydrophobic”. A well-defined pharmacophore model includes both volumes and hydrogen bond vectors. As a pharmacophore model should be able to discriminate between molecules with and without bioactivity, the set of molecules should include both active and inactive compounds. Conformational analysis – Generate a set of low energy conformations that is likely to contain the bioactive conformation for each of the selected molecules, molecular superimposition – Superimpose all combinations of the low-energy conformations of the molecules. Similar functional groups common to all molecules in the set might be fitted, the set of conformations that results in the best fit is presumed to be the active conformation. Abstraction – Transform the superimposed molecules into an abstract representation, for example, superimposed phenyl rings might be referred to more conceptually as an aromatic ring pharmacophore element. Likewise, hydroxy groups could be designated as a hydrogen-bond donor/acceptor pharmacophore element, validation – A pharmacophore model is a hypothesis accounting for the observed biological activities of a set of molecules that bind to a common biological target. The model is only valid insofar as it is able to account for differences in activity of a range of molecules. As the biological activities of new molecules become available, the model can be updated to further refine it. In modern computational chemistry, pharmacophores are used to define the features of one or more molecules with the same biological activity. A database of chemical compounds can then be searched for more molecules which share the same features arranged in the same relative orientation. Pharmacophores are also used as the point for developing 3D-QSAR models. Historically, pharmacophores were established by Lemont Kier, who first mentions the concept in 1967, the development of the concept is often erroneously accredited to Paul Ehrlich. However neither the source nor any of his other works mention the term pharmacophore or make use of the concept
26.
Metabotropic glutamate receptor 5
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Metabotropic glutamate receptor 5 is a G protein-coupled receptor that in humans is encoded by the GRM5 gene. The amino acid L-glutamate is the major excitatory neurotransmitter in the nervous system. Glutamatergic neurotransmission is involved in most aspects of brain function. Group I includes GRM1 and GRM5 and these receptors have shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7, Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Alternative splice variants of GRM8 have been described but their nature has not been determined. In addition to the site at least two distinct allosteric binding sites exist on the mGluR5. A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, has developed to date. CHPG Lithium LY-344,545 Mavoglurant Remeglurant SIB-1893 ADX-47273 CPPHA VU-29, Ki =244 nM, EC50 =9.0 nM, VU-36, Ki =95 nM, EC50 =10.6 nM VU-1545, Ki =156 nM, EC50 =9. This suggested that the receptor may be involved in the rewarding properties of cocaine. However, a study showed that mGluR5 knockout mice responded the same to cocaine reward as wild type mice demonstrated by a cocaine place-preference paradigm. This evidence taken together shows that mGluR5 may be crucial for drug-related instrumental self-administration learning, Metabotropic glutamate receptor Metabotropic Glutamate Receptors, mGlu5. IUPHAR Database of Receptors and Ion Channels, international Union of Basic and Clinical Pharmacology. This article incorporates text from the United States National Library of Medicine, which is in the public domain
27.
WIN-35428
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-2-β-Carbomethoxy-3-β-tropane is a stimulant drug used in scientific research. CFT is a phenyltropane based dopamine reuptake inhibitor and is derived from cocaine. It is around 3-10x more potent than cocaine and lasts around 7 times longer based on animal studies, the tartrate is another salt form that is reported. CFT was first reported by Clarke and co-workers in 1973 and this drug is known to function as a positive reinforcer. Tritiated CFT is frequently used to map binding of ligands to the DAT. Radiolabelled forms of CFT have been used in humans and animals to map the distribution of dopamine transporters in the brain. CFT was found to be useful for this application as a normal fluorine atom can be substituted with the radioactive isotope 18F which is widely used in Positron emission tomography. CFT is about as addictive as cocaine in animal studies, but is less often due to its longer duration of action. Potentially this could make it a drug to be used as a substitute for cocaine. In August 2010, some sources claimed that the designer drug Ivory Wave contained WIN35,428. However, samples of Ivory Wave have been found to contain MDPV, administering 100 mg/kg of CFT to rats only resulted in convulsions being reported, whereas CIT had the ability to cause death at this dose. WIN35, 065-2 List of phenyltropanes List of cocaine analogues DMello GD, Goldberg DM, Goldberg SR, conditioned taste aversion and operant behaviour in rats, effects of cocaine and a cocaine analogue. Sershen H, Lajtha A. Saturable cocaine binding in central nervous system of mouse, spealman, RD, Bergman, J, Madras, BK. Self-administration of the high-affinity cocaine analog 2 beta-carbomethoxy-3 beta-tropane, milius, RA, Saha, JK, Madras, BK, Neumeyer, JL. Synthesis and Receptor Binding of N-Substituted Tropane Derivatives, high- Affinity Ligands for the Cocaine Receptor. Cline, EJ, Scheffel, U, Boja, JW, Carroll, FI, Katz, JL, Kuhar, behavioral effects of novel cocaine analogs, a comparison with in vivo receptor binding potency. Journal of Pharmacology and Experimental Therapeutics, singh S. Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. 100, 925-1024 Li, SM, Campbell, BL, Katz, interactions of cocaine with dopamine uptake inhibitors or dopamine releasers in rats discriminating cocaine
28.
Phenyltropane
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For an enumeration of their multiple types see list of phenyltropanes. Phenyltropanes were originally developed to reduce cocaine addiction and dependency, in general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a position in this field, they are not the only researchers that have prepared these analogues. The phenyltropane compounds were discovered by R. Clarke et al. during research to try and dissociate the stimulant properties of cocaine from its abuse. The first simple phenyltropanes to be made were shown to be active in behavioral assays only for the ββ-isomers, the activity of the corresponding αβ-isomers was disappointing. It was later shown that WIN 35065-2 and WIN34,428 are mostly dopamine selective reuptake inhibitors with some residual actions at the norepinephrine transporter, the neurotransmitter dopamine is a key candidate for explanation of reinforcing actions drugs. Its unclear to which extent NET is involved in the actions of cocaine. Animal studies show evidence that inhibiting the SERT might reduce cocaine intake, animal studies on monkeys and rats have tried to assess the self-administration propensity of phenyltropane analogs alongside cocaine. Frequently the analogs are administered prior to the start of a session to see if they can suppress cocaine lever responding, most of the analogs behave in ways that might be considered typical for a DRI. In particular, they tend to stimulate locomotor activity, and cause nonselective reductions in cocaine intake relative to food, at the dose that can reduce cocaine intake, most of the analogs require a high DAT occupancy. This would mean that the agonists would need to be active at the dose that can bring about reductions in cocaine craving. Most of the analogs will readily substitute for cocaine, although most do not elicit as many lever responses per session because of pharmacokinetic factors, since these agonists function as reinforcers, there is an obvious concern surrounding their abuse liability. Nevertheless, an onset, long-duration agonist seems like a reasonable approach. RTI-336 is an example of a phenyltropane that is being explored in the context of a treatment for cocaine addiction. RTI-336 is a DRI and thus specifically targets the DAT which is responsible for the properties of cocaine. Although there may be a role for NET inhibition and acetylcholinergic actions, dopamine is a biological precursor to noradrenaline. DA is made from tyrosine, which is an amino acid given that it can be made from phenylalanine. The more greatly attested habit creating methamphetamine is more serotonergic than the lesser reinforcing amphetamine, most modern research suggests that 5-HT is negatively correlated with the addiction forming potential of psychostimulants, this is not saying that SRI properties cannot be considered beneficial
29.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
30.
Journal of Medicinal Chemistry
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The Journal of Medicinal Chemistry is a peer-reviewed medical journal covering research in medicinal chemistry. It is published by the American Chemical Society and it was established in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry and obtained its current name in 1963. They succeeded Philip S. Portoghese in 2012, Portoghese had served as editor-in-chief from 1972-2011. According to the Journal Citation Reports, the journal had a 2014 impact factor of 5.447, ranking it 3rd out of 59 journals in the category Chemistry, Medicinal