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
Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant, used in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant. Mianserin is related to mirtazapine, both chemically and in terms of its actions and effects, although there are significant differences between the two drugs. Mianserin at higher doses is used for the treatment of major depressive disorder, it can be used at lower doses to treat insomnia. It should not be given to be people younger than 18 years old, as it can increase the risk of suicide attempts and suicidal thinking, it can increase aggressiveness. While there is no evidence that it can harm a fetus from animal models, there is no data showing it safe for pregnant women to take. People with severe liver disease should not take mianserin, it should be used with caution for people with epilepsy or who are at risk for seizures, as it can lower the threshold for seizures. Common adverse effects include constipation, dry mouth, drowsiness at the beginning of treatment.
Common adverse effects include drowsiness during maintenance therapy, headache, dizziness and weakness. Uncommon adverse effects include weight gain. Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, panic attacks, decreased appetite or anorexia, diarrhea and vomiting, flu-like symptoms, such as allergies or pruritus, among others. Overdose of mianserin is known to produce sedation, hypotension or hypertension, QT interval prolongation. Mianserin may make drugs that have effects on the brain, like alcohol, anxiolytics and antipsychotics, have stronger effects, it can make antiepileptic medicines work less well. People should not take monoamine oxidase inhibitors and mianserin at the same time. Carbamazepine and phenobarbital will cause the body to metabolize mianserin faster and may reduce its effects. There is a risk of dangerously low blood pressure if people take mianserin along with diazoxide, hydralazine, or nitroprusside. Mianserin can make antimuscarinics have stronger effects.
Mianserin should not be taken with apraclonidine, sibutramine, or the combination drug of artemether with lumefantrine. Mianserin appears to exert its effects via antagonism of histamine and serotonin receptors, inhibition of norepinephrine reuptake. More it is an antagonist/inverse agonist at most or all sites of the histamine H1 receptor, serotonin 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, 5-HT7 receptors, adrenergic α1- and α2-adrenergic receptors, additionally a norepinephrine reuptake inhibitor; as an H1 receptor inverse agonist with high affinity, mianserin has strong antihistamine effects. Conversely, it has low affinity for the muscarinic acetylcholine receptors, hence lacks anticholinergic properties. Mianserin has been found to be a low affinity but significant partial agonist of the κ-opioid receptor to some tricyclic antidepressants. Blockade of the H1 and α1-adrenergic receptors has sedative effects, antagonism of the 5-HT2A and α1-adrenergic receptors inhibits activation of intracellular phospholipase C, which seems to be a common target for several different classes of antidepressants.
By antagonizing the somatodendritic and presynaptic α2-adrenergic receptors which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine and acetylcholine in various areas of the brain and body. Along with mirtazapine, although to a lesser extent in comparison, mianserin has sometimes been described as a noradrenergic and specific serotonergic antidepressant. However, the actual evidence in support of this label has been regarded as poor; the bioavailability of mianserin is 20 to 30%. Its plasma protein binding is 95%. Mianserin is metabolized in the liver by the CYP2D6 enzyme via N-demethylation, its elimination half-life is 21 to 61 hours. The drug is excreted 14 to 28 % in feces. Mianserin is a tetracyclic piperazinoazepine. --Mianserin is 200–300 times more active than its enantiomer --mianserin. It was not discovered by Organon International. Investigators conducting clinical trials in the US submitted fraudulent data, it was never approved in the US.
Mianserin was one of the first antidepressants to reach the UK market, less dangerous than the tricyclic antidepressants in overdose. Mianserin is the English and German generic name of the drug and its INN and BAN, while mianserin hydrochloride is its USAN, BANM, JAN, its generic name in French and its DCF are miansérine, in Spanish and Italian and its DCIT are mianserina, in Latin is mianserinum. Mianserin is marketed in many countries under the brand name Tolvon, it is available throughout the world under a variety of other brand names including Athymil, Deprevon, Lerivon, Serelan and Tolvin among others. Mianserin is not approved for use in the United States, but is available in the United Kin
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse. Reuptake is necessary for normal synaptic physiology because it allows for the recycling of neurotransmitters and regulates the level of neurotransmitter present in the synapse, thereby controlling how long a signal resulting from neurotransmitter release lasts; because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific transport proteins are necessary for the reabsorption of neurotransmitters. Much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake; the first primary sequence of a reuptake protein was published in 1990. The technique for protein sequence determination relied upon the purification and cloning of the transporter protein in question, or expression cloning strategies in which transport function was used as an assay for cDNA species coding for that transporter.
After separation, it was realized. Further exploration in the field of reuptake proteins found that many of the transporters associated with important neurotransmitters within the body were very similar in sequence to the GABA and norepinephrine transporters; the members of this new family include transporters for dopamine, serotonin, proline and GABA. They were called Na+/Cl− dependent neurotransmitter transporters. Sodium and chloride ion dependence will be discussed in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family. In addition to this, the N- and C-termini exist in the intracellular space; these proteins all have an extended extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labeling experiments verified the predicted topological organization of the serotonin transporter. In addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter:Sodium Symporters.
One of these proteins, LeuT, from Aquifex aeolicus, was crystallized by Yamashita et al. with high resolution, revealing a molecule of leucine and two Na+ ions bound near the center of the protein. They found that the transmembrane helices 1 and 6 contained unwound segments in the middle of the membrane. Along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites; the crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6-10. There is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position. External and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8.
The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron. Typical neurotransmitter sodium symport transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane; the ions flow down their concentration gradients, in many cases leading to transmembrane charge movement, enhanced by the membrane potential. These forces pull the neurotransmitter substrate into the cell against its own concentration gradient. At a molecular level, Na+ ions stabilize amino acid binding at the substrate site and hold the transporter in an outward-open conformation that allows substrate binding; the role of the Cl− ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na+. After ion and substrate binding have taken place, some conformational change must occur. From the conformational differences between the structure of TMs 1-5 and that of TMs 6-10, from the identification of a substrate permeation pathway between the binding site of SERT and the cytoplasm, a mechanism for conformational change was proposed in which a four-helix bundle composed of TMs 1, 2, 6 and 7 changes its orientation within the rest of the protein.
A structure of LeuT in the inward-open conformation subsequently demonstrated that the major component of the conformational change represents movement of the bundle relative to the rest of the protein. The main objective of a reuptake inhibitor is to decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, increasing the concentration of neurotransmitter in the synapse; this increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the neuronal system in question, a reuptake inhibitor can have drastic effects on cognition and behavior. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of these inhibitors in the extracellular permeation pathway. However, the competitive nature of serotonin transport inhibition by antidepressants suggests that in neurotransmitter transporters, they bind in a site overlapping the substrate site. Horschitz et al. examined reuptake inhibitor selectivity among the rat serotonin reuptake protein expressed in human em
Levomilnacipran is an antidepressant, approved in the United States in 2013 for the treatment of major depressive disorder in adults. It is the levorotatory enantiomer of milnacipran, has similar effects and pharmacology, acting as a serotonin–norepinephrine reuptake inhibitor; the FDA approved levomilnacipran for the treatment of major depressive disorder based on the results of one 10-week phase II and four 8-week phase III clinical trials. Four of the five trials demonstrated a statistically significant superiority to placebo as measured by the Montgomery–Åsberg Depression Rating Scale. Superiority to placebo was demonstrated by improvement in the Sheehan Disability Scale. Side effects seen more with levomilnacipran than with placebo in clinical trials included nausea, sweating, insomnia, increased heart rate and blood pressure, urinary hesitancy, erectile dysfunction and delayed ejaculation in males, vomiting and palpitations. Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine.
To demonstrate, the serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 14:1, milnacipran = 1.6:1, levomilnacipran = 1:2. The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear, but may include improved effectiveness, though increased side effects. Levomilnacipran is selective for the serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites. However, it does show some affinity for the dizocilpine site of the NMDA receptor, has been found to inhibit NR2A and NR2B subunit-containing NMDA receptors with respective IC50 values of 5.62 and 4.57 µM. As such, levomilnacipran is an NMDA receptor antagonist at high concentrations. Levomilnacipran has been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1, responsible for β-amyloid plaque formation, hence may be a useful drug in the treatment of Alzheimer's disease. Levomilnacipran has a high oral bioavailability of 92% and a low plasma protein binding of 22%.
It is metabolized in the liver by the cytochrome P450 enzyme CYP3A4, thereby making the medication susceptible to grapefruit-drug interactions. The drug has an elimination half-life of 12 hours, allowing for once-daily administration. Levomilnacipran is excreted in urine. Levomilnacipran was developed by Forest Laboratories and Pierre Fabre Group, was approved by the Food and Drug Administration in July 2013. Media related to Levomilnacipran at Wikimedia Commons Fetzima Official Site
Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on efficacy, they are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial – their approval does not mean that the therapy is'safe' or effective, only that the trial may be conducted. Depending on product type and development stage, investigators enroll volunteers or patients into small pilot studies, subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, they can involve a single research center or multiple centers, in one country or in multiple countries.
Clinical study design aims to ensure the scientific reproducibility of the results. Costs for clinical trials can range into the billions of dollars per approved drug; the sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become an approved drug; some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to patients with specific health conditions who are willing to try an experimental treatment; when participants are healthy volunteers who receive financial incentives, the goals are different than when the participants are sick. During dosing periods, study subjects remain under supervision for one to 40 nights. Pilot experiments are conducted to gain insights for design of the clinical trial to follow.
There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy" or "effectiveness". Neither is an absolute criterion; the benefits must outweigh the risks. For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care, are used for a life-threatening condition. In the US, the elderly constitute 14 % of the population. People over 55 are excluded from trials because their greater health issues and drug use complicate data interpretation, because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are frequently excluded. Pregnant women are excluded due to potential risks to the fetus; the sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type of patients might benefit.
If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, whether improvement or worsening of the condition targeted by the study drug occurs; the researchers send the data to the trial sponsor, who analyzes the pooled data using statistical tests. Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: On a specific kind of patient, for example, a patient, diagnosed with Alzheimer's disease At varying dosages, for example, a 10 milligram dose instead of a 5 milligram dose For a new indication Evaluation for improved efficacy in treating a patient's condition as compared to the standard therapy for that condition Evaluation of the study drug or device relative to two or more approved/common interventions for that condition, for example, device A versus device B, or therapy A versus therapy B)While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo.
Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures that all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects; as a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method the experimental step. The most common clinical trials evaluate new pharmaceutical products, medical devices, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation. To drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket appr
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
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.