This is a working overview of receptor agonist, written for readers who want more than a one-paragraph summary but less than a textbook.
Reviewed 2026-04-18. Anything still debated is marked as such rather than presented as settled.
Receptor activation raises intracellular cyclic AMP through Gs coupling, which promotes glucose-dependent insulin release and suppresses glucagon secretion when blood glucose is elevated. Effects outside the pancreas include slower gastric emptying and altered appetite signalling in the hypothalamus and hindbrain. The relative contribution of each tissue to overall metabolic outcomes remains an area of active investigation. Central mechanisms in particular are inferred mainly from animal models and indirect human measures rather than direct observation.
Serum protein binding dominates the pharmacokinetic profile. The attached chain associates strongly with albumin, shielding the peptide from enzymatic attack and slowing filtration by the kidney. This interaction extends the circulation half-life to roughly one week in humans, which supports weekly administration intervals. An oral version pairs the peptide with an absorption enhancer that transiently alters gastric epithelium, permitting limited uptake; bioavailability by that route is substantially lower than by injection.
Semaglutide belongs to the glucagon-like peptide-1 receptor agonist class, a group of synthetic peptides that imitate an incretin hormone released by intestinal L cells after food intake. Native GLP-1 circulates for only a few minutes because dipeptidyl peptidase-4 cleaves it rapidly. The hormone acts on pancreatic islets, the gastrointestinal tract, and several brain regions. Because the natural peptide is short-lived, development work concentrated on analogues that keep receptor activity while resisting enzymatic breakdown and renal clearance.
序列层面的改动同时解决了两个问题，即酶解稳定性与肾脏清除速度。天然 GLP-1 在循环中的半衰期仅约两分钟，主要被二肽基肽酶-4 迅速灭活。酰化侧链与白蛋白的可逆结合形成循环储库，使分子缓慢释放并持续激活受体。这种设计思路后来被广泛用于同类长效肽的开发，属于该类药物化学改造的典型范式。
Semaglutide 是一种经结构修饰的胰高血糖素样肽-1 类似物，其主链与内源性 GLP-1(7-36) 约有百分之九十四的序列一致性。第 8 位丙氨酸被 α-氨基异丁酸取代，使二肽基肽酶-4 无法识别原有切割位点。第 34 位赖氨酸换为精氨酸，进一步降低酶解速率。第 26 位赖氨酸经间隔基连接一条含十八个碳的二酸脂肪链，该侧链赋予分子与血浆白蛋白结合的能力。
| Property | Value | Notes |
|---|---|---|
| Molecular class | Synthetic peptide, GLP-1 receptor agonist | 31 amino acid residues |
| Molecular formula | C187H291N45O59 | free peptide, no counter-ion |
| Approximate mass | 4114 Da | matches theoretical value |
| Receptor target | Glucagon-like peptide-1 receptor | Gs-coupled, cyclic AMP pathway |
| Circulation half-life | About one week in humans | extended by albumin association |
Stability studies examine how temperature, pH, and moisture influence degradation rates over time. In aqueous solution, hydrolysis and deamidation accelerate as pH moves away from mildly acidic conditions. Light exposure and residual metal ions can also trigger oxidation of susceptible residues. Accelerated aging at elevated temperature is used to estimate shelf life, though extrapolation to room temperature carries uncertainty because individual degradation pathways do not always scale predictably.
Lyophilized semaglutide powder is typically held at minus twenty degrees Celsius for long-term storage. At that temperature, solid-state degradation reactions proceed slowly and the peptide remains intact for extended periods. Repeated freeze-thaw cycles are best avoided because they promote aggregation and can shift the proportion of monomeric peptide present. Working aliquots are often prepared so that each portion is thawed only once, and desiccant is placed inside the vial to limit moisture uptake.
Reported molecular weight is approximately 4113.6 daltons for the free base, and the peptide is supplied as a lyophilized powder or in buffered liquid form depending on the intended use. It is freely soluble in water when formulated with appropriate excipients, though the unconjugated peptide shows limited stability at neutral pH over long periods. Analytical characterization typically relies on reversed-phase high-performance liquid chromatography and mass spectrometry. Purity specifications for research-grade material commonly exceed ninety-five percent by area. Isotopic and impurity profiles differ between suppliers.
Two principal therapeutic variants exist under separate regulatory filings, one indicated for glycemic control in type 2 diabetes and one for chronic weight management. Both use the same active molecule; differences lie in formulation strength, titration schedule, and labeling. Regulatory agencies in the United States and European Union approved injectable forms in 2017 and 2018 respectively. An oral tablet formulation received approval later, using a carrier molecule to enhance absorption across the gastric epithelium. Labeling differs by jurisdiction and by indication.
The distinction between established facts and open questions matters here. That the peptide binds the GLP-1 receptor and stimulates insulin release in a glucose-dependent manner is well documented. How individual variability in receptor density, gastric emptying rate, and gut microbiome composition shapes response remains an active research area. Long-term outcomes beyond five years of continuous use are not yet fully characterized in published trials, and several extension studies are ongoing.
Pharmacological activity arises from agonism at the glucagon-like peptide-1 receptor, a G protein-coupled receptor expressed in the pancreas, the gastrointestinal tract, and the brainstem. Receptor activation raises intracellular cyclic adenosine monophosphate and enhances insulin release in a glucose-dependent manner, an effect that diminishes when blood glucose concentration is low. Other effects include slowed gastric emptying and hypothalamic satiety signalling. These pathways are described well. Receptor desensitisation rates across tissues, relative to the endogenous hormone, are still under investigation, and reported findings differ between laboratories.
The company that developed the compound filed it as a long-acting analogue, and it gained first approval in 2017 for type 2 diabetes. Later authorisations from several regulators extended the indication to chronic weight management, and the World Health Organization added the glucagon-like peptide-1 receptor agonist drug class to its model list of essential medicines in 2023. Production uses solid-phase peptide synthesis followed by side-chain conjugation and chromatographic purification. Supply constraints and cost differences across regions are well documented. Literature on long-term outcomes continues to grow, with many trials reporting surrogate endpoints rather than hard clinical endpoints.
Semaglutide is a synthetic peptide of thirty-one amino acids that shares roughly ninety-four percent sequence identity with human glucagon-like peptide-1. Two substitutions resist enzymatic cleavage by dipeptidyl peptidase-4, and a fatty diacid side chain attached through a linker promotes binding to serum albumin. That albumin binding slows renal clearance and extends the circulating half-life from minutes to approximately one week. The structural changes are well established in the published literature. Whether the same modifications affect receptor signalling bias in ways that matter clinically remains an open question.
Two structural features account for the prolonged half-life of semaglutide. A modified amino acid at position 8 resists cleavage by dipeptidyl peptidase-4, the enzyme that rapidly degrades native GLP-1. A fatty diacid side chain binds serum albumin, which limits renal clearance and protects the peptide from enzymatic breakdown. These modifications yield a plasma half-life of approximately one week in humans, allowing once-weekly administration. The relationship between plasma concentration and clinical effect varies between individuals, and sources of that variability are still being characterized.
Semaglutide is a synthetic peptide analog of glucagon-like peptide-1 (GLP-1), a hormone released from intestinal L-cells after food intake. The compound belongs to the incretin mimetic class and acts at GLP-1 receptors distributed across pancreatic, gastrointestinal, cardiovascular, and central nervous system tissues. Compared with native GLP-1, the molecule carries structural changes that extend its activity from minutes to roughly one week. It is studied for glycemic control in type 2 diabetes and for weight management, and its effects on cardiovascular and other outcomes remain active research areas.
=== Prevalence and trends === Cocaine production, seizures, and use all reached record levels in 2023, making it the world's fastest-growing illicit drug market. Seizures rose by 68% from 2019 to 2023, while the number of users increased from 17 million in 2013 to 25 million in 2023, according to the UNODC World Drug Report 2025. Concurrently, record levels of cocaine production have enabled traffickers to enter new markets across Asia and Africa, reflecting the expanding global reach of cocaine trafficking. The U.S. is disproportionately the world's largest consumer of cocaine, while South America, collectively as a continent, ranks third in terms of consumer market size. Europe ranks cocaine as the second most commonly used illicit drug. Cocaine is among the most widely consumed recreational stimulants worldwide.
== RCM Beynon Prize == To mark the 80th birthday of John H. Beynon, the founding Editor of RCM, in 2004 an annual award was established in his honour by the publishers. The award is made on the recommendation of an ad hoc Sub-committee of the editorial board of RCM.
== History == The therapeutic efficacy of subcutaneous pegcetacoplan in treating paroxysmal nocturnal hemoglobinuria has been established through several clinical trials. Initial phase I and II trials, such as PADDOCK, PALOMINO, and PHAROAH, evaluated pegcetacoplan in participants with paroxysmal nocturnal hemoglobinuria who had not received a complement inhibitor or had previously received eculizumab. These trials demonstrated that 1–2 years of pegcetacoplan treatment effectively controlled hemolysis and improved quality of life in participants with paroxysmal nocturnal hemoglobinuria. Building upon these findings, the efficacy of pegcetacoplan was further assessed in phase III trials. The PRINCE trial, a 26-week study, focused on complement inhibitor-naïve participants with paroxysmal nocturnal hemoglobinuria, while the PEGASUS trial, a 48-week multinational study, included complement inhibitor-treated participants with paroxysmal nocturnal hemoglobinuria. In these trials, subcutaneous pegcetacoplan was administered at a dosage of 1080 mg twice weekly, delivered as a 20-mL subcutaneous infusion. Participants had the option to self-administer the medication or have it administered by qualified research personnel.
The Grainyhead-like (Grhl) gene family is a group of highly conserved transcription factors, which work to regulate the expression of specific target genes. Grainyhead (Grh) was originally identified in Drosophila as being implicated within development through its role of regulating numerous genetic pathways. While Drosophila has only one Grh gene, there are three homologues currently known across other species (Grhl1-3). It appears that all members of the Grhl gene family are involved in epidermal barrier integrity, including its formation and repair, and are tightly regulated to prevent physical defects. The Grhl family of genes are found in a range of organisms, from humans to fish and fungi, and all have similar roles to each other in regards to the developmental processes that they have a role in regulating. This could indicate that the Grhl genes could be one of the earliest genes to arise within our genome, providing vital functions for survival of an early common ancestor.
As a consequence of the September 11 attacks, American forces immediately increased their readiness to the highest level in 28 years, closing the blast doors of the NORAD's Cheyenne Mountain Operations Center for the first time due to a non-exercise event. But unlike similar increases during the Cold War, Russia immediately decided to stand down a large military exercise in the Arctic region, in order to minimize the risk of incidents, rather than following suit. The former chair of the United Nations disarmament committee stated that there are more than 16,000 strategic and tactical nuclear weapons ready for deployment and another 14,000 in storage, with the U.S. having nearly 7,000 ready for use and 3,000 in storage, and Russia having about 8,500 ready for use and 11,000 in storage. In addition, China is thought to possess about 400 nuclear weapons, Britain about 200, France about 350, India about 80–100, and Pakistan 100–110. North Korea is confirmed as having nuclear weapons, though it is not known how many, with most estimates between 1 and 10. Israel is also widely believed to possess usable nuclear weapons. NATO has stationed about 480 American nuclear weapons in Belgium, the Netherlands, Italy, Germany, and Turkey, and several other nations are thought to be in pursuit of an arsenal of their own. Pakistan's nuclear policy was significantly affected by the 1965 war with India. The 1971 war and India's nuclear program played a role in Pakistan's decision to go nuclear. India and Pakistan both decided not to participate in the NPT.
Sources: en.wikipedia.org
==== Czech Republic ==== Possession of more than 200 mg of 2C-B is punishable with a two years jail sentence. Smaller amount is punishable by a fine. The 200 mg threshold is merely a guideline which the court can reconsider depending on circumstances.
The following classification system for transmembrane solute transporters has been constructed in the TCDB. Three families of ABC exporters are defined by their evolutionary origins. ABC1 exporters evolved by intragenic triplication of a 2 TMS precursor (TMS = transmembrane segment. A "2 TMS" protein has 2 transmembrane segments) to give 6 TMS proteins. ABC2 exporters evolved by intragenic duplication of a 3 TMS precursor, and ABC3 exporters evolved from a 4 TMS precursor which duplicated either extragenicly to give two 4 TMS proteins, both required for transport function, or intragenicly to give 8 or 10 TMS proteins. The 10 TMS proteins appear to have two extra TMSs between the two 4 TMS repeat units. Most uptake systems (all except 3.A.1.21) are of the ABC2 type, divided into type I and type II by the way they handle nucleotides. A special subfamily of ABC2 importers called ECF use a separate subunit for substrate recognition. ABC1 (InterPro: IPR036640): ABC2 (InterPro: IPR000412 [partial]): ABC3 (InterPro: IPR003838):
The investigation by Science and the NIH was triggered by whistleblowers who delivered a 113 page dossier to Science. The dossier presented evidence that patients treated with 3K3A-APC died at a higher rate in the first week following treatment than those on the placebo (6 out of 66 versue 1 out 44). Also, patients on the drug suffered more disability. The dossier also claimed that data had been doctored in dozens of papers from Zlokovic's lab. Wade Smith, a University of California, San Francisco neurologist and StrokeNet principal investigator said that “I think pausing the trial until any impact of potential impropriety in preclinical drug testing is resolved to ensure the compound is safe for humans is the correct pathway to follow. This drug may work in humans so discarding it would be a shame,” he adds. “Alternatively, moving forward with a compound that may be unsafe is worse.”
Outer Membrane Vesicle (OMV) vaccines contain the outer membrane of a bacterium without any of its internal components or genetic material. Thus, ideally, they stimulate an immune response effective against the original bacteria without the risk of an infection. Genetic vaccines deliver nucleic acid that codes for an antigen into host cells, which then produce that antigen, stimulating an immune response. This category of vaccine includes DNA vaccines, RNA vaccines, and viral vector vaccines, which differ in the chemical form of nucleic acid and how it is delivered into host cells. A variety of vaccine types are under development; see Experimental Vaccine Types. Most vaccines are given by hypodermic or intramuscular injection as they are not absorbed reliably through the gut. Live attenuated polio and some typhoid and cholera vaccines are given orally in order to produce immunity based in the bowel.
However, it indicated a poisoning effect on modification of strontium. Some bismuth alloys, such as Bi35-Pb37-Sn25, are combined with nonsticking materials such as mica, glass, and enamels because they easily wet them, allowing to make joints to other parts. Addition of bismuth to caesium enhances the quantum yield of caesium cathodes. Sintering of bismuth and manganese powders at 300 °C (572 °F) produces a permanent magnet and magnetostrictive material, which is used in ultrasonic generators and receivers working in the 10–100 kHz range and in magnetic and holographic memory devices.
Sources: en.wikipedia.org
Barnes (December 2002). "Road Work: Racial Profiling and Drug Interdiction on the Highway". Michigan Law Review (Submitted manuscript). 101 (3): 653–751. doi:10.2307/1290469. JSTOR 1290469. Beckett, Katherine; Nyrop, Kris; Pfingst, Lori; Bowen, Melissa (August 2005). "Drug Use, Drug Possession Arrests, and the Question of Race: Lessons from Seattle". Social Problems. 52 (3): 419–441. doi:10.1525/sp.2005.52.3.419. Banks, R. Richard (December 2003). "Beyond Profiling: Race, Policing, and the Drug War". Stanford Law Review. 56 (3): 571. Stephanie R. Bush-Baskette (2004). "12. "The War on Drugs as a War on Black Women"". In Meda Chesney-Lind; Lisa Pasko (eds.). Girls, women, and crime: selected readings. SAGE. ISBN 978-0-7619-2828-7. Ruiz, Jim; Woessner, Matthew (Autumn 2006). "Profiling, Cajun style: racial and demographic profiling in Louisiana's war on drugs". International Journal of Police Science & Management. 8 (3): 176–197. doi:10.1350/ijps.2006.8.3.176. S2CID 145127716. Illya Lichtenberg (March 2006). "Driving While Black (DWB): Examining Race as a Tool in the War on Drugs". Police Practice & Research. 7 (1): 49–60. doi:10.1080/15614260600579649. S2CID 143784397. Katherine Beckett; Kris Nyrop; Lori Pfingst (February 2006). "Race, Drugs, and Policing: Understanding Disparities in Drug Delivery Arrests". Criminology. 44 (1): 105–137. doi:10.1111/j.1745-9125.2006.00044.x. Bobo, Lawrence D.; Victor Thompson (Summer 2006). "Unfair By Design: The War on Drugs, Race, and the Legitimacy of the Criminal Justice System" (PDF). Social Research. 73 (2): 445–472.
=== Water footprint === One ton of hide or skin generally produces 20 to 80 m3 of waste water, including chromium levels of 100–400 mg/L, sulfide levels of 200–800 mg/L, high levels of fat and other solid wastes, and notable pathogen contamination. Producers often add pesticides to protect hides during transport. With solid wastes representing up to 70% of the wet weight of the original hides, the tanning process represents a considerable strain on water treatment installations.
Twenty chemical elements are known to be required to support human biochemical processes by serving structural and functional roles, and there is evidence for a few more. Oxygen, hydrogen, carbon and nitrogen are the most abundant elements in the body by weight and make up about 96% of the weight of a human body. Calcium makes up 920 to 1200 grams of adult body weight, with 99% of it contained in bones and teeth. This is about 1.5% of body weight. Phosphorus occurs in amounts of about 2/3 of calcium, and makes up about 1% of a person's body weight. The other major minerals (potassium, sodium, chlorine, sulfur and magnesium) make up only about 0.85% of the weight of the body. Together these eleven chemical elements (H, C, N, O, Ca, P, K, Na, Cl, S, Mg) make up 99.85% of the body. The remaining ≈18 ultratrace minerals comprise just 0.15% of the body, or about one hundred grams in total for the average person. Total fractions in this paragraph are amounts based on summing percentages from the article on chemical composition of the human body. Some diversity of opinion exist about the essential nature of various ultratrace elements in humans (and other mammals), even based on the same data. For example, whether chromium is essential in humans is debated. No Cr-containing biochemical has been purified. The United States and Japan designate chromium as an essential nutrient, but the European Food Safety Authority (EFSA), representing the European Union, reviewed the question in 2014 and does not agree.
While the prevalent explanation for osmolyte action relies on excluded volume effects that are entropic in nature, circular dichroism (CD) experiments have shown osmolyte to act through an enthalpic effect. The molecular mechanism for their role in protein stabilization is still not well established, though several mechanisms have been proposed. Computer molecular dynamics simulations suggest that osmolytes stabilize proteins by modifying the hydrogen bonds in the protein hydration layer. Several studies have shown that hydrogen bonds play an important role for the stability between subunits in multimeric proteins. For example, a study of sorbitol dehydrogenase displayed an important hydrogen bonding network which stabilizes the tetrameric quaternary structure within the mammalian sorbitol dehydrogenase protein family. A protein backbone hydrogen bond incompletely shielded from water attack is a dehydron. Dehydrons promote the removal of water through proteins or ligand binding. The exogenous dehydration enhances the electrostatic interaction between the amide and carbonyl groups by de-shielding their partial charges. Furthermore, the dehydration stabilizes the hydrogen bond by destabilizing the nonbonded state consisting of dehydrated isolated charges. Wool, being a protein fibre, is held together by hydrogen bonds, causing wool to recoil when stretched. However, washing at high temperatures can permanently break the hydrogen bonds and a garment may permanently lose its shape.
=== Ascending === Here the solvent travels up the chromatographic paper. Both descending and ascending paper chromatography are used for the separation of organic and inorganic substances. The sample and solvent move upward.
Sources: en.wikipedia.org
It is a synthetic peptide of 31 amino acids, built to resemble the natural incretin hormone GLP-1. Because of its size and composition it is handled analytically like other therapeutic peptides, using chromatographic and mass spectrometric methods rather than the techniques typical of small organic drugs.
The substitution at position 8 removes the site recognised by dipeptidyl peptidase-4, the enzyme that destroys the native hormone within minutes. The linked lipophilic chain then binds circulating albumin, which further limits access by degradative enzymes and reduces renal loss. Together these features lengthen the effective circulation time considerably.
It acts at the glucagon-like peptide-1 receptor, a G protein-coupled receptor that signals mainly through cyclic AMP. Activation is glucose dependent, meaning insulin release is stimulated more strongly when blood glucose is already elevated. Other tissues carrying the same receptor respond as well, which explains effects beyond glucose control.
差别集中在三处：第 8 位残基被非天然氨基酸取代，第 34 位换成精氨酸，第 26 位增加一条脂肪酸侧链。前两处改动降低酶解速率，侧链则通过白蛋白结合延长循环时间。综合结果是半衰期从约两分钟延长到约一周。