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Discovery And Development Of Beta2 Agonists
β2-adrenoceptor agonists is a group of drugs that act selectively on β2-receptors in the lungs causing bronchodilation. β2-agonists are used to treat asthma and COPD, diseases that cause obstruction in the airways. Prior to their discovery, the non-selective beta-agonist isoprenaline was used. The aim of the drug development through the years has been to minimise side effects, achieve selectivity and longer duration of action. The mechanism of action is well understood and has facilitated the development. The structure of the binding site and the nature of the binding is also well known, as is the structure activity relationship. History The β2-selective agonists were developed in the 20th century and are a very valuable class of drugs. In 1901 Jōkichi Takamine isolated the hormone adrenalin, also known as epinephrine. In 1890 adrenalin was first given to asthma patients orally. It had little or no effect because it is metabolized in the digestive tract and is deactivate ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Beta2-adrenergic Agonist
Beta2-adrenergic agonists, also known as adrenergic β2 receptor agonists, are a class of drugs that act on the β2 adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation. β2 adrenergic agonists' effects on smooth muscle cause dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin. They are primarily used to treat asthma and other pulmonary disorders, such as Chronic obstructive pulmonary disease (COPD). Mechanism of action Activation of β adrenergic receptors leads to relaxation of smooth muscle in the lung, and dilation and opening of the airways. β adrenergic receptors are coupled to a stimulatory G protein of adenylyl cyclase. This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes inactivate myosin light-chain kinase and ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Long-acting Beta-adrenoceptor Agonist
Long-acting β adrenoceptor agonists (LABAs, more specifically, long-acting β2 adrenergic receptor agonists) are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β2 agonists such as salbutamol (albuterol), as they have a duration of action of approximately 12 hours in comparison with the 4-to-6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β2 agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecu ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types. There are two types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), which are also known as white and brown fat, respectively, and comprise two types of fat cells. Structure White fat cells White fat cells contain a single large lipid droplet surrounded by a layer of cytoplasm, and are known as unilocular. The nucleus is flattened and pushed to the periphery. A typical fat cell is 0.1 mm in diameter with some being twice that size, and others half that size. However, these numerical estimates of fat cell size depend largely on the measurement method and the location of the adipose tissue. The fat stored i ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Beta-3 Adrenergic Receptor
The beta-3 adrenergic receptor (β3-adrenoceptor), also known as ADRB3, is a beta-adrenergic receptor, and also denotes the human gene encoding it. Function Actions of the β3 receptor include *Enhancement of lipolysis in adipose tissue. *Thermogenesis in skeletal muscle Page 163 It is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Some β3 agonists have demonstrated antistress effects in animal studies, suggesting it also has a role in the central nervous system (CNS). β3 receptors are found in the gallbladder, urinary bladder, and in brown adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat. In the urinary bladder it is thought to cause relaxation of the bladder and prevention of urination. Mechanism of action Beta adrenergic receptors are involved in the epinephrine- and norepinephrine-induced activation of adenylate cyclas ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Beta-2 Adrenergic Receptor
The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increased cAMP, and downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation. Robert J.Lefkowitz and Brian Kobilka studied beta 2 adrenergic receptor as a model system which rewarded them the 2012 Nobel Prize in Chemistry “for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein-coupled-receptors”. The official symbol for the human gene encoding the β2 adrenoreceptor is ''ADRB2''. Gene The gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes. Structure The ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Beta-1 Adrenergic Receptor
The beta-1 adrenergic receptor (β1 adrenoceptor), also known as ADRB1, is a beta-adrenergic receptor, and also denotes the human gene encoding it. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein and is expressed predominantly in cardiac tissue. Receptor Actions Actions of the β1 receptor include: The receptor is also present in the cerebral cortex. Agonists Isoprenaline has higher affinity for β1 than adrenaline, which, in turn, binds with higher affinity than noradrenaline at physiologic concentrations. Selective agonists to the beta-1 receptor are: *Denopamine * Dobutamine (in cardiogenic shock) *Xamoterol (cardiac stimulant) Antagonists ''(Beta blockers)'' β1-selective antagonists include: *Acebutolol (in hypertension, angina pectoris and arrhythmias) *Atenolol (in hypertension, coronary heart disease, arrhythmias and myocardial infarction) *Betaxolol (in hypertension and glaucoma) *Bisoprolol (in hypertension, coronary h ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Adrenergic Receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example. Many cells have these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system (SNS). The SNS is responsible for the fight-or-flight response, which is triggered by experiences such as exercise or fear-causing situations. This response dilates pupils, increases heart rate, mobilizes energy, and diverts blood flow from non-essential organs to skeletal muscle. These effects together tend to increase physical performance momentarily. History By the turn of the 19th century, it was agreed that the stimulation of sympathetic nerves could cause d ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
G Protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases. There are two classes of G proteins. The first function as monomeric small GTPases (small G-proteins), while the second function as heterotrimeric G protein complexes. The latter class of complexes is made up of ''alpha'' (α), ''beta'' (β) and ''gamma'' (γ) subunits. In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the beta-gamma complex . Heterotrimeric G proteins located within the cell are ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Beta2Receptor-with-Gs
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiodental fricative while in borrowed words is instead commonly transcribed as μπ. Letters that arose from beta include the Roman letter and the Cyrillic letters and . Name Like the names of most other Greek letters, the name of beta was adopted from the acrophonic name of the corresponding letter in Phoenician, which was the common Semitic word ''*bait'' ('house'). In Greek, the name was ''bêta'', pronounced in Ancient Greek. It is spelled βήτα in modern monotonic orthography and pronounced . History The letter beta was derived from the Phoenician letter beth . Uses Algebraic numerals In the system of Greek numerals, beta has a value of 2. Such use is denoted by a number mark: Β′. Computing Finance Beta is used ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Elimination Reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one- or two-step mechanism. The one-step mechanism is known as the E2 reaction, and the two-step mechanism is known as the E1 reaction. The numbers refer not to the number of steps in the mechanism, but rather to the kinetics of the reaction: E2 is bimolecular (second-order) while E1 is unimolecular (first-order). In cases where the molecule is able to stabilize an anion but possesses a poor leaving group, a third type of reaction, E1CB, exists. Finally, the pyrolysis of xanthate and acetate esters proceed through an "internal" elimination mechanism, the Ei mechanism. E2 mechanism The E2 mechanism, where E2 stands for bimolecular elimination, involves a one-step mechanism in which ''carbon-hydrogen'' and ''carbon-halogen'' bonds break to form a double bond (''C=C Pi bond''). The specifics of the reaction are as follows: * E2 is a single step elimination, ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Monoamine Oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first such enzyme was discovered in 1928 by Mary Bernheim in the liver and was named tyramine oxidase. The MAOs belong to the protein family of flavin-containing amine oxidoreductases. MAOs are important in the breakdown of monoamines ingested in food, and also serve to inactivate monoamine neurotransmitters. Because of the latter, they are involved in a number of psychiatric and neurological diseases, some of which can be treated with monoamine oxidase inhibitors (MAOIs) which block the action of MAOs. Subtypes and tissue distribution In humans there are two types of MAO: MAO-A and MAO-B. * Both are found in neurons and astroglia. * Outside the central nervous system: ** MAO-A is also found in the liver, pulmonary vascular endotheliu ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
COMT
Catechol-''O''-methyltransferase (COMT; ) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-''O''-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957. Function Catechol-''O''-methyltransferase is involved in the inactivation of the catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine). The enzyme introduces a methyl group to the catecholamine, which is donated by S-adenosyl methionine (SAM). Any compound having ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
