Jmol
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, or for research e.g. in chemistry and biochemistry. It is written in the programming language Java, so it can run on the operating systems Windows, macOS, 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 wide range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile, Chemical Markup Language. There is 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, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1
5-HT receptor
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both inhibitory neurotransmission; the serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand. The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, epinephrine / norepinephrine, acetylcholine, as well as many hormones, including oxytocin, vasopressin, cortisol and substance P, among others; the serotonin receptors influence various biological and neurological processes such as aggression, appetite, learning, mood, nausea and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, anorectics, gastroprokinetic agents, antimigraine agents and entactogens. Serotonin receptors are found in all animals and are known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems. They can be divided into 7 families of G protein-coupled receptors except for the 5-HT3 receptor, a ligand-gated ion channel, which activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. In 2014, a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae, named pr5-HT8, it does not occur in mammals and shares low similarity to the known 5-HT receptor classes. The 7 general serotonin receptor classes include a total of 14 known serotonin receptors; the specific types have been characterized as follows: Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor. Nonselective agonists of 5-HT receptor subtypes include ergotamine, which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors.
LSD is a 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist. The genes coding for serotonin receptors are expressed across the mammalian brain. Genes coding for different receptors types follow different developmental curves. There is a developmental increase of HTR5A expression in several subregions of the human cortex, paralleled by a decreased expression of HTR1A from the embryonic period to the post-natal one. A number of receptors were classed as "5-HT1-like" - by 1998 it was being argued that, since these receptors were "a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7" receptors the classification was redundant. 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. Rubenstein LA, Lanzara RG. "Activation of G protein-coupled receptors entails cysteine modulation of agonist binding". Cogprints. Retrieved 2008-04-11. Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM.
"5-HT radioligands for human brain imaging with PET and SPECT". Med Res Rev. 33: 54–111. Doi:10.1002/med.20245. PMC 4188513. PMID 21674551
Upjohn
The Upjohn Company was a pharmaceutical manufacturing firm founded in 1886 in Kalamazoo, Michigan, by Dr. William E. Upjohn, an 1875 graduate of the University of Michigan medical school; the company was formed to make friable pills, which were designed to be digested. These could be "reduced to a powder under the thumb", a strong marketing argument at the time. In 1995, Upjohn merged with Pharmacia AB, to form Upjohn. Upjohn developed a process for the large scale production of cortisone; the oxygen atom at the 11 position in this steroid is an absolute requirement for biological activity. There are however no known natural sources for starting materials; the only method for preparing this drug prior to 1952 was a lengthy synthesis starting from cholic acid isolated from bile. In 1952 two Upjohn biochemists, Dury Peterson and Herb Murray announced that they were able to introduce this crucial oxygen atom by fermentation of the steroid progesterone with a common mold of the genus Rhizopus. Over the next several years a group of chemists headed by John Hogg developed a process for preparing cortisone from the soybean sterol stigmasterol.
The microbiological oxygenation is a key step in this process. Subsequently, Upjohn together with Schering biochemically converted cortisone into the more potent steroid prednisone by a bacterial fermentation. In chemical research, the company is best known for the development of the Upjohn dihydroxylation by V. VanRheenen, R. C. Kelly and D. Y. Cha in 1976. Upjohn's most well-known drugs before the acquisition by Pfizer were Xanax, Motrin and Rogaine. W. E. Upjohn Institute for Employment Research Upjohn Co. v. United States Memories of The Upjohn Company http://www.michmarkers.com/startup.asp?startpage=S0582.htm
4-Methylthioamphetamine
4-Methylthioamphetamine is a designer drug of the substituted amphetamine class developed in the 1990s by a team led by David E. Nichols, an American pharmacologist and medical chemist, at Purdue University, it acts as a non-neurotoxic selective serotonin releasing agent in animals. 4-MTA is the methylthio derivative of amphetamine. In 1997 three unrelated death because of drugs got reported to the Forensic Science Laboratory of the Netherlands; the substance in question was a new ring-substituted amphetamine derivative. In 1998 two additional cases of this still unknown compound were added to the list, the incidents were reported to the IPSC. In both the Netherlands and Swiss the unknown compound was encountered as in the hydrochloride salt form, pictures of the different tablets were compared to each other. After an investigation, it appeared that in other European countries such as the United Kingdom and Germany the derivative was encountered; the new drug got as far as Australia. After analytical research, the compound was identified as 4-methylthioamphetamine.
This was an known compound only intended for pharmacological studies on animals. The studies of 4-MTA by David Nichols were linked to the tablets found in all the different countries. 4-MTA was developed by the research team led by David E. Nichols but was intended to be used only as an agent for laboratory research into the serotonin transporter protein. Nichols was sad to see 4-MTA appear as a drug of abuse on the street, he said after finding out his research was used as a dangerous serotonin releasing drugs, "I was stunned. I had published information led to human death." Nichols intentions were to discover how MDMA worked in the brain to find a positive use for it in psychotherapy. Nichols studied thereby molecules with similar structure, including 4-MTA. Between 1992 and 1997 they published three papers on the effects of this drug in rats and the idea that it could be used in the treatment of depression and be a potential replacement for Prozac. Without the knowledge of Nichols and his team, others synthesized the drugs into a tablet.
These tablets were known by their street name, named ‘flatliners’, Nichols’ laboratory had published that the rats experienced the same euphoric effects as ecstasy, the motivation for its production and distribution to humans. Nichols said, "I have never considered my research to be dangerous, in fact hoped one day to develop medicines to help people." Because of the 4-MTA relating death, Nichols' laboratory was asked to study the human effects of other materials they have studied, to avoid situation as with 4-MTA. Most of the molecules the laboratory further had published could not kill in reasonable dosages; the typical tablets sold on the street contained between 100–140 mg 4-MTA. 4-MTA was sold in smart shops in the Netherlands, though was soon banned by the Dutch government after serious side-effects started to emerge. The Union of Smartshop Owners decided to leave it out of their assortiment after they discovered the drug had only been tested on rats, it was briefly sold on the black market as MDMA during the late 1990s in the US, but proved unpopular due to its high risk of severe side effects and relative lack of positive euphoria.
4-MTA is a strong serotonin releaser similar to paramethoxyamphetamine, which can cause pronounced hyperthermia resulting in organ failure and death. Therefore, the major neuropharmacological effect is an increased release of serotonin, the inhibition of serotonin uptake of mono oxidase A; the combination of the releasing of serotonin from neurons, but the prevention of breaking this neurotransmitter down again, leads to dangerous serotonin syndrome. The serotonin syndrome is a hyper serotonergic state, which can be become fatal and is an side effect of serotonergic enhancing drugs; the symptoms of serotonin syndrome are described in the Report on the Risk Assessment of 4-MTA Symptoms of serotonin syndrome Euphoria Drowsiness Sustained rapid eye movement Overreaction of the reflexes Rapid muscle contraction and relaxation in the ankle causing abnormal movements of the foot Clumsiness Restlessness Feeling drunk and dizzy Muscle contraction and relaxation in the jaw Sweating Intoxication Muscle twitching Rigidity High body temperature Mental status changes are frequent ShiveringAnother effect is the increase of the secretion of several hormones, like adrenocorticotropic hormone, prolactin and renin induced by 4-MTA through stimulation of serotonergic neurotransmission.
There has been suggested that 4-MTA because of its slow onset of action, is more dangerous than other designer drugs. Abusers of the drug take another dose because they assume the first was inadequate; the only 4 studies that are conducted show a weak effect on noradrenaline. This study was executed with a single dose of 4-MTA, no study where the effect of multiple doses 4-MTA where researched exist up to date. In a procedure analogous to the production of other amphetamines, 4-MTA has been prepared from 4-phenylacetone by the Leuckart reaction and the reaction byproducts have been characterized. 4-MTA undergoes limited biotransformation, the metabolic pathways of the metabolites in humans is postulated in the following steps: β-Hydroxylation of the side chain to 4-hydroxy-4-me
Cannabidiol
Cannabidiol is a phytocannabinoid discovered in 1940. It is one of some 113 identified cannabinoids in cannabis plants, accounting for up to 40% of the plant's extract; as of 2018, preliminary clinical research on cannabidiol included studies of anxiety, movement disorders, pain. Cannabidiol can be taken into the body in multiple ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, by mouth, it may be supplied as CBD oil containing only CBD as the active ingredient, a full-plant CBD-dominant hemp extract oil, dried cannabis, or as a prescription liquid solution. CBD does not have the same psychoactivity as THC, may affect the actions of THC. Although in vitro studies indicate CBD may interact with different biological targets, including cannabinoid receptors and other neurotransmitter receptors, as of 2018 the mechanism of action for its biological effects has not been determined. In the United States, the cannabidiol drug Epidiolex has been approved by the Food and Drug Administration for treatment of two epilepsy disorders.
The side effects of long-term use of the drug include somnolence, decreased appetite, fatigue, weakness, sleeping problems. The U. S. Drug Enforcement Administration has assigned Epidiolex a Schedule V classification, while non-Epidiolex CBD remains a Schedule I drug prohibited for any use. Cannabidiol is not scheduled under any United Nations drug control treaties, in 2018 the World Health Organization recommended that it remain unscheduled. There has been little high-quality research into the use of cannabidiol for epilepsy, what there is is limited to refractory epilepsy in children. While the results of using medical-grade cannabidiol in combination with conventional medication shows some promise, they did not lead to seizures being eliminated, were associated with some minor adverse effects. An orally administered cannabidiol solution was approved by the US Food and Drug Administration in June 2018 as a treatment for two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.
Preliminary research on other possible therapeutic uses for cannabidiol include several neurological disorders, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice. Preliminary research indicates that cannabidiol may reduce adverse effects of THC those causing intoxication and sedation, but only at high doses. Safety studies of cannabidiol showed it is well-tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects. Epidiolex documentation lists sleepiness and poor quality sleep, decreased appetite and fatigue. Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent manner. In vitro, cannabidiol inhibited receptors affecting the activity of voltage-dependent sodium and potassium channels, which may affect neural activity. A small clinical trial reported that CBD inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC.
Little is known about potential drug interactions but CBD-mediates decrease in clobazam metabolism. Cannabidiol has low affinity for the cannabinoid CB2 receptors. Cannabidiol may be an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor, expressed in the caudate nucleus and putamen in the brain, it may act as an inverse agonist of GPR3, GPR6, GPR12. CBD has been shown to act as a serotonin 5-HT1A receptor partial agonist, this action may be involved in its antidepressant and neuroprotective effects, it is an allosteric modulator of the μ- and δ-opioid receptors as well. The pharmacological effects of CBD may involve PPARγ intracellular calcium release; the oral bioavailability of CBD is 13 to 19%, while its bioavailability via inhalation is 11 to 45%. The elimination half-life of CBD is 18–32 hours. Cannabidiol is metabolized in the liver as well as in the intestines by CYP2C19 and CYP3A4 enzymes, UGT1A7, UGT1A9, UGT2B7 isoforms. CBD may have a wide margin in dosing.
Nabiximols is a patented medicine containing THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat central neuropathic pain in multiple sclerosis, in 2007 for cancer related pain. In New Zealand, Sativex is "approved for use as an add-on treatment for symptom improvement in people with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication." Cannabidiol is soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid. In basic media and the presence of air, it is oxidized to a quinone. Under acidic conditions it cyclizes to THC, which occurs during pyrolysis; the synthesis of cannabidiol has been accomplished by several research groups. Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase. Cannabinoids were isolated from the cannabis plant in 1940 by Roger Adams, its chemical structure was established in 1963.
Cannabidiol is the generic name of the drug and its INN. Food and beverage products containing CBD were introduced in the United States in 2017. Similar to energy drinks and protein bars which may contain vitamin or herbal additives and beverage items can be infused with CBD as an alternative means of ingesting the substance. In the United S
Dopamine
Dopamine is an organic chemical of the catecholamine and phenethylamine families. It functions both as a hormone and a neurotransmitter, 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, synthesized in the brain and kidneys. Dopamine is synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells; the brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones; these pathways and cell groups form a dopamine system, neuromodulatory.
In popular culture and media, dopamine is seen as the main chemical of pleasure, but the current opinion in pharmacology is that dopamine instead confers motivational salience. Outside the central nervous system, dopamine functions as a local paracrine messenger. In blood vessels, it acts as a vasodilator. With the exception of the blood vessels, dopamine in each of these peripheral systems is synthesized locally and exerts its effects near the cells that release it. Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, some of the key medications used to treat them work by altering the effects of dopamine. Parkinson's disease, a degenerative 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. There is evidence that schizophrenia involves altered levels of dopamine activity, most antipsychotic drugs used to treat this are dopamine antagonists which reduce dopamine activity.
Similar dopamine antagonist drugs are 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. Dopamine itself is available as a manufactured medication for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock in newborn babies. A dopamine molecule consists of a catechol 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 benzene ring with this amine attachment makes it a substituted phenethylamine, a family that includes numerous psychoactive drugs. Like most amines, dopamine is an organic base; as a base, it is protonated in acidic environments.
The protonated form is water-soluble and stable, but can become oxidized if exposed to oxygen or other oxidants. In basic environments, dopamine is not protonated. In this free base form, it is less water-soluble and more reactive; because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine hydrochloride—that is, the hydrochloride salt, created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine colorless powder. Dopamine is synthesized in a restricted set of cell types neurons and cells in the medulla of the adrenal glands; the primary and minor metabolic pathways are: Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine Minor: L-Phenylalanine → m-Tyrosine → m-Tyramine → DopamineThe direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine.
These amino acids are found in nearly every protein and so are available in food, with tyrosine being the most common. Although dopamine is found in many types of food, it is incapable of crossing the blood–brain barrier that surrounds and protects the brain, it must therefore be synthesized inside the brain to perform its neuronal activity. L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, iron as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, with pyridoxal phosphate as the cofactor. Dopamine itself is used as precursor in the synthesis o
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the 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 been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open 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 considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of 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; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is 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, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
