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.
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may be considered ligands which display both agonistic and antagonistic effects—when both a full agonist and partial agonist are present, the partial agonist acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. Clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present; some common drugs that have been classed as partial agonists at particular receptors include buspirone, buprenorphine and norclozapine. Examples of ligands activating peroxisome proliferator-activated receptor gamma as partial agonists are honokiol and falcarindiol.
Delta 9-tetrahydrocannabivarin is a partial agonist at CB2 receptors and this activity might be implicated in ∆9-THCV-mediated anti-inflammatory effects. Competitive antagonist Intrinsic sympathomimetic activity of beta blockers Inverse agonist Mixed agonist/antagonist
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of two forms of long-term energy reserves, with the other form being triglyceride stores in adipose tissue. In humans, glycogen is made and stored in the cells of the liver and skeletal muscle. In the liver, glycogen can make up 5–6% of the organ's fresh weight, the liver of an adult weighing 70 kg can store 100–120 grams of glycogen. In skeletal muscle, glycogen is found in a low concentration and the skeletal muscle of an adult weighing 70 kg stores 400 grams of glycogen; the amount of glycogen stored in the body—particularly within the muscles and liver—mostly depends on physical training, basal metabolic rate, eating habits. Small amounts of glycogen are found in other tissues and cells, including the kidneys, red blood cells, white blood cells, glial cells in the brain.
The uterus stores glycogen during pregnancy to nourish the embryo. 4 grams of glucose are present in the blood of humans at all times. Glycogen stores in skeletal muscle serve as a form of energy storage for the muscle itself. Liver glycogen stores serve as a store of glucose for use throughout the body the central nervous system; the human brain consumes 60% of blood glucose in fasted, sedentary individuals. Glycogen is the analogue of starch, a glucose polymer that functions as energy storage in plants, it is more extensively branched and compact than starch. Both are white powders in their dry state. Glycogen is found in the form of granules in the cytosol/cytoplasm in many cell types, plays an important role in the glucose cycle. Glycogen forms an energy reserve that can be mobilized to meet a sudden need for glucose, but one, less compact than the energy reserves of triglycerides; as such it is found as storage reserve in many parasitic protozoa. Glycogen is a branched biopolymer consisting of linear chains of glucose residues with an average chain length of 8–12 glucose units.
Glucose units are linked together linearly by α glycosidic bonds from one glucose to the next. Branches are linked to the chains from which they are branching off by α glycosidic bonds between the first glucose of the new branch and a glucose on the stem chain. Due to the way glycogen is synthesised, every glycogen granule has at its core a glycogenin protein. Glycogen in muscle and fat cells is stored in a hydrated form, composed of three or four parts of water per part of glycogen associated with 0.45 millimoles of potassium per gram of glycogen. Glucose is an osmotic molecule, can have profound effects on osmotic pressure in high concentrations leading to cell damage or death if stored in the cell without being modified. Glycogen is a non-osmotic molecule, so it can be used as a solution to storing glucose in the cell without disrupting osmotic pressure; as a meal containing carbohydrates or protein is eaten and digested, blood glucose levels rise, the pancreas secretes insulin. Blood glucose from the portal vein enters liver cells.
Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase. Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases. After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, glycogen synthesis stops; when it is needed for energy, glycogen is converted again to glucose. Glycogen phosphorylase is the primary enzyme of glycogen breakdown. For the next 8–12 hours, glucose derived from liver glycogen is the primary source of blood glucose used by the rest of the body for fuel. Glucagon, another hormone produced by the pancreas, in many respects serves as a countersignal to insulin. In response to insulin levels being below normal, glucagon is secreted in increasing amounts and stimulates both glycogenolysis and gluconeogenesis. Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells.
Other cells that contain small amounts use it as well. As muscle cells lack glucose-6-phosphatase, required to pass glucose into the blood, the glycogen they store is available for internal use and is not shared with other cells; this is in contrast to liver cells, which, on demand do break down their stored glycogen into glucose and send it through the blood stream as fuel for other organs. Glycogen was discovered by Claude Bernard, his experiments showed that the liver contained a substance that could give rise to reducing sugar by the action of a "ferment" in the liver. By 1857, he described the isolation of a substance he called "la matière glycogène", or "sugar-forming substance". Soon after the discovery of glycogen in the liver, A. Sanson found that muscular tissue contains glycogen; the empirical formula for glycogen of n was established by Kekulé in 1858. Glycogen synthesis is, unlike its breakdown, endergonic
Flushing is to become markedly red in the face and other areas of the skin, from various physiological conditions. Flushing is distinguished, despite a close physiological relation between them, from blushing, milder restricted to the face, cheeks or ears, assumed to reflect emotional stress, such as embarrassment, anger, or romantic stimulation. Flushing is a cardinal symptom of carcinoid syndrome—the syndrome that results from hormones being secreted into systemic circulation. Abrupt cessation of physical exertion abdominal cutaneous nerve entrapment syndrome in patients who have had abdominal surgery alcohol flush reaction antiestrogens such as tamoxifen atropine poisoning body contact with warm or hot water butorphanol reaction with some narcotic analgesics caffeine consumption carbon monoxide poisoning carcinoid tumor chronic obstructive pulmonary disease emphysema cluster headache attack or headache compression of the nerve by the sixth thoracic vertebrae coughing severe coughing fits Cushing's syndrome dehydration dysautonomia emotions: anger, embarrassment fever Kratom fibromyalgia high doses of non flush free niacin histamines homocystinuria Horner's syndrome hot flush hyperglycaemia hyperstimulation of the parasympathetic nervous system the vagus nerve hyperthyroidism inflammation iron poisoning Jarisch-Herxheimer reaction keratosis pilaris rubra faceii Limerence mastocytosis medullary thyroid cancer mixing an antibiotic with alcohol pheochromocytoma polycythemia vera powerful vasodilators, such as dihydropyridine calcium channel blockers rosacea severe pain sexual arousal orgasm sexual intercourse sneezing some recreational drugs, such as alcohol, heroin and amphetamines spicy foods sunburn tachycardia vinpocetine Allergies Commonly referred to as the sex flush, vasocongestion of the skin can occur during all four phases of the human sexual response cycle.
Studies show that the sex flush occurs in 50–75% of females and 25% of males, yet not consistently. The sex flush tends to occur more under warmer conditions and may not appear at all under lower temperatures. During the female sex flush, pinkish spots develop under the breasts spread to the breasts, face, soles of the feet, over the entire body. Vasocongestion is responsible for the darkening of the clitoris and the walls of the vagina during sexual arousal. During the male sex flush, the coloration of the skin develops less than in the female, but starts with the epigastrium, spreads across the chest continues to the neck, forehead and sometimes, shoulders and forearms; the sex flush disappears soon after reaching orgasm, but in other cases it may take up to two hours or so, sometimes intense sweating occurs simultaneously. Cholinergic urticaria Erythema Pallor Rash
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding; the majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, villain, rival", derived from anti- and agonizesthai.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly; the activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses; this may be accomplished by binding to the allosteric site. In addition, antagonists may interact at unique binding sites not involved in the biological regulation of the receptor's activity to exert their effects.
The term antagonist was coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s; the current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by'blocking' the receptor from the agonist; this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states; the discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, antagonists inhibit the function of agonists, inverse agonists, partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.
The potency of an antagonist is defined by its half maximal inhibitory concentration. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar; the lower the IC50 the greater the potency of the antagonist, the lower the concentration of drug, required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects; the affinity of an antagonist for its binding site, i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used.
However, it is important. The effects of receptor desensitization on reaching equilibrium must als