Receptor antagonist

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

Oka River

Oka is a river in central Russia, the largest right tributary of the Volga. It flows through the regions of Oryol, Kaluga, Ryazan and Nizhny Novgorod and is navigable over a large part of its total length, as far upstream as to the town of Kaluga, its length exceeds 1,500 kilometres. The Russian capital Moscow sits on one of the Oka's tributaries—the Moskva River; the Oka river is the homeland of the Eastern Slavic Vyatichi tribe. By 5th century the land around the Oka river was inhabited by different Slavic tribes; the Baltic tribe of Galindians lived in the western part of the Oka basin. Turkic tribes inhabited the Oka area; the Oka river was inhabited by Vikings and people from Northern lands like for example Scandinavia. Artefacts of Scandinavian origin were found along the Oka - Volga route. There is no common opinion. From the Mongol conquest until about 1633, the Oka was the last line of defense against steppe raiders; the river gave its name to the Upper Oka Principalities, situated upstream from Tarusa.

In 1221 Grand Duke Yuri II of Vladimir founded Nizhny Novgorod to become one of the largest Russian cities, to protect the Oka's confluence with the Volga. The Qasim Khanate, a Muslim polity, occupied the middle reaches of the Oka in the 15th and 16th centuries. Before the construction of the railways in the mid-19th century and the building of the Moscow Canal in the 1930s, the Oka, along with its tributary Moskva, served as an important transportation route connecting Moscow with the Volga River. Due to the Oka's and Moskva's meandering courses, travel was not fast: for example, it took Cornelis de Bruijn around 10 days to sail from Moscow down these two rivers to Nizhny Novgorod in 1703. Traveling upstream may have been slower, as the boats had to be pulled by burlaks; the banks of the river are dotted with historical and cultural sites, including the medieval monasteries of Murom, the mosques and minarets of Kasimov, the fortified kremlins of Kolomna and Serpukhov, the memorial houses of Vasily Polenov and Sergey Yesenin, the excavated ruins of Old Ryazan and the Oka Shukhov Tower.

The Prioksko-Terrasny Biosphere Reserve lies along the left bank of the river opposite the town of Pushchino and is known for its wisent breeding nursery. Oryol Ugra Zhizdra Upa Protva Nara Moskva Pra Osyotr Pronya Para Moksha Tyosha Klyazma Besputa Oryol Belyov Chekalin Kaluga Aleksin Tarusa Serpukhov Stupino Kashira Protvino Pushchino Kolomna Ryazan Kasimov Murom Pavlovo Navashino Gorbatov Dzerzhinsk Nizhny Novgorod The River appears as the title and main theme in a popular, nostalgia filled song of the Polish 1st Tadeusz Kościuszko Infantry Division, formed nearby in 1943; the unit fought all the way to Berlin alongside the Red Army. It was written by Leon Pasternak. Oka at GEOnet Names Server Media related to Oka River at Wikimedia Commons

Taiyō no nai Machi

Taiyō no nai Machi is a Japanese novel written by Sunao Tokunaga. Taiyō no nai Machi is a proletarian novel by Sunao Tokunaga, it was first published in serialized form in the literary magazine Senki between June and November of 1929. The novel was inspired by Tokunaga's experiences being fired from his job at a printing company following his participation in a labour strike in 1926, he began writing the novel in 1928. Different accounts of the origins of the work were presented by Fusao Hayashi in his 1955 memoirs and Tokunaga himself in a 1930 essay. Literary historian Donald Keene places more trust in Hayashi's account, presented below. In the spring of 1929, Tokunaga presented an early manuscript to Hayashi, an acquaintance, glad to assist the writing career of a working-class author. Hayashi was distressed about the writing style of the work, which resembled that of a popular magazine, but Tokunaga responded with the concern that proletarian readers would be unable to understand a work written in a more literary style.

Hayashi suggested Tokunaga rewrite the book, loaning him a copy of a Japanese translation of Fyodor Gladkov's 1925 novel Cement and recommending he follow Gladkov's writing style. Tokunaga admitted to Hayashi a few days that he had read Cement but would be unable to mimic Gladkov's style. Hayashi offered to rewrite the opening to provide Tokunaga with a model, going on to rewrite the first ten or so pages and extensively revise the rest. After Tokunaga presented the completed work to Hayashi, Hayashi recommended it to the publishers of Senki. Taiyō no nai Machi was well received on initial publication, selling 40,000 copies and turning Tokunaga into the first writer of the proletarian movement whose book was so successful as to allow him to build a house on the proceeds. Contemporary proletarian writer Shigeharu Nakano praised the work as a rare well-written novel by a member of the working class. Keene called the work Tokunaga's "most important work". While noting that the work has been critically acclaimed, Keene himself dismisses it as "not a good novel" relying on "stock types" of characters being placed in "implausibly melodramatic situations."

The work was translated into German in 1930 and Russian in 1932, before going on to appear in several other European languages