4474-91-3

Basic information

• Product Name: ANGIOTENSIN II, HUMAN
• Synonyms: DRVYIHPF;[ILE5]-ANGIOTENSIN 2;HYPERTENSION II HUMAN;L-ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE;H-ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-OH;FLUORESCEIN-NHCS-NH-ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-OH;ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-OH 2CH3CHOOH H2O;ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE ACOH 4H2O
• CAS NO: 4474-91-3
• Molecular Formula: C₅₀H₇₁N₁₃O₁₂
• Molecular Weight: 1046.18
• EINECS: 2017-001-1
• Product Categories: peptide;Angiotensin
• Mol File: 4474-91-3.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 809.08°C (rough estimate)
• Appearance: orange/Powder
• Density: 1.1257 (rough estimate)
• Refractive Index: 1.6700 (estimate)
• Storage Temp.: −20°C
• Solubility: insoluble in DMSO; insoluble in EtOH; ≥100.2 mg/mL in H2O
• PKA: pK1: 10.37 (25°C)
• Water Solubility: Soluble in Water (25 mg/ml), and 5% Acetic Acid (1 mg/ml).
• CAS DataBase Reference: ANGIOTENSIN II, HUMAN(CAS DataBase Reference)
• NIST Chemistry Reference: ANGIOTENSIN II, HUMAN(4474-91-3)
• EPA Substance Registry System: ANGIOTENSIN II, HUMAN(4474-91-3)

Safety Data

• WGK Germany: 3
• RTECS: BW2165000
• Hazardous Substances Data: 4474-91-3(Hazardous Substances Data)

Usage

Discovery

Angiotensin II?is the active peptide hormone of the reninangiotensin system (RAS) with broad functions, including a vasopressor effect and thirst stimulation. It is a drug target for hypertension and renal diseases.?In 1940, two groups of researchers separately discovered a potent vasoconstrictor by incubating plasma with renin; the substance was named both “angiotonin” and “hypertensin.” In 1958, they agreed to rename it “angiotensin” (angio=blood vessel; tensin=tension).

Structure

Ang II is a linear peptide with no known secondary modification.?Ang II is produced by the subsequent cleavage of angiotensinogen (AGT) by renin and angiotensin I (Ang I) by ACE (See Renin Angiotensin System).?Mr. 1046 of Ang II in humans. Freely soluble in water.

Gene, mRNA, and mRNA

AGT is located on chromosome 1q42.2 in humans. AGT belongs to the SERPIN family A, member 8. AGT protein sequences are highly variable but the functional domains (Ang I) are relatively conserved among vertebrates. Ang I sequences were identified by the incubation of a renin source (kidney extract) and an angiotensinogen source (plasma). Lamprey Ang I with sequence NRVYVHPFTL was first sequenced using peptide purification. However, the lamprey genome data suggested a different Ang I sequence, and was later confirmed as the native AGT. The purified teleost-type Ang I produced in the buccal gland was suggested to be involved in endocrine mimicry to reduce host immunorejection.

Agonist

A nonpeptide ligand, L-162,313 was shown to bind to AT1A, AT1B, and the AT2 receptor and act as an agonist on AT1A and AT1B receptors in mice (34.9 and 23.3% of the maximum response of Ang II, respectively). Early studies used CGP42112A as the agonist for the AT2 receptor but compound 21, with little affinity for the AT1 receptor, was recently developed as a specific agonist of the AT2 receptor in humans.

Antagonist

Saralasin ([Sar1 ], [Ala8 ]-Ang II) is a partial agonist of angiotensin II receptors, though it is commonly mistaken as a competitive antagonist. Antagonists including losartan, irbesartan, olmesartan, candesartan, and valsartan are commonly used clinically as AT1 blockers. Two AT2 receptor antagonists, PD123177 (discontinued) and PD123319 (available), were developed to inhibit AT2 activities.

Biological functions

Ang II/AT1 axis mediates vasoconstriction, thirst, release of vasopressin and aldosterone, renal sodium reabsorption, fibrosis, inflammation, angiogenesis, vascular aging, and atherosclerosis. Ang II-induced effects included blood pressure control; drinking; adrenergic stimulation; modulation of the ion pump and transporter activities in the gill, kidney, and intestine in fish; control of the filtering nephron population in fish; and regulation of ventral skin absorption in amphibians. The injection of Ang II significantly increased ventral skin drinking in the frog. Lamprey Ang II is a vasodepressor instead of a vasopressor when injected intraarterially. The intracerebroventricular (ICV) injection of Ang II into the trout increased the systemic blood pressure, heart rate, and ventilation rate. The ICV injection of Ang II elicits tachycardia in contrast to bradycardia when injected peripherally. Central Ang II injection also inhibits the vagal-mediated baro-reflex, indicating that brain RAS is involved in the heart rate control.The AT2 receptor is mostly embryonic. The expression decreases in adults and is confined in certain tissues such as the kidney. The effects of AT2 are often antagonistic to AT1, and activation of the AT2 receptor usually indicates a pathophysiological condition of AT1-mediated action with potential harmful consequences. AT2 is abundantly expressed in the spleen of the adult eel, which suggests an immune-related function.

Description

Different sources of media describe the Description of 4474-91-3 differently. You can refer to the following data:
1. It is known that tumor tissues including metastatic lymph nodes are composed of newly growing vessels which lack blood flow autoregulation and are influenced only secondarily by the responding somatic vessels. Human angiotensin II (AT II). a vasopressor, was introduced in Japan to improve the efficacy of systemic chemotherapy. In patients with various advanced cancers, i.v. infusion of AT II to achieve a mean blood pressure of 1.5 times of baseline (but not over 150 mm Hg) followed by a bolus injection of conventional cytotoxic agents increases blood flow 5-7 fold in tumor tissues and therefore, increases drug delivery to the target tissue resulting in enhanced chemotherapeutic effects. This induced-hypertension chemotherapy regimen can be performed safely with minimal side effects.
2. Angiotensin II is a peptide hormone known best as a vasoconstrictor with central roles in chronic hypertension, heart failure, and stroke. It is an octapeptide typically generated by the removal of two residues from angiotensin I by angiotensin-converting enzyme (ACE). Angiotensin II is a ligand for at least two distinct receptors, AT1 and AT2, each evoking distinct signaling pathways and physiological responses. The development of antagonists for specific angiotensin II receptor subtypes represents a valuable alternative to ACE inhibitors.

Originator

Toa Eiyo (Japan)

Uses

Different sources of media describe the Uses of 4474-91-3 differently. You can refer to the following data:
1. Cardiopulmonary resuscitation - not yet an approved application
2. A peptide involved in the regulation of blood pressure
3. Angiotensin II is a peptide hormone known best as a vasoconstrictor with central roles in chronic hypertension, heart failure, and stroke. It is an octapeptide typically generated by the removal of two residues from angiotensin I by angiotensin-converting enzyme (ACE). Angiotensin II is a ligand for at least two distinct receptors, AT1 and AT2, each evoking distinct signaling pathways and physiological responses. The development of antagonists for specific angiotensin II receptor subtypes represents a valuable alternative to ACE inhibitors.

Brand name

Delivert

General Description

Functions in blood pressure maintenance. Stimulates the release of aldosterone from the adrenal gland. Has strong vasoconstrictive effects. Increases the entry of Ca2+ in heart muscle via voltage-sensitive channels and activates myosin light chain kinase. Activates JAK2 in smooth muscle cells. Activates p125FAK and a cytosolic 115-120 kDa calcium-dependent tyrosine kinase in rat epithelial cells. Also activates pp60c-src in vascular smooth muscle cells. Inhibits adenylate cyclase activity in spontaneously hypertensive rats.

Biochem/physiol Actions

Product does not compete with ATP.

Clinical Use

Renin antagonists, ACE inhibitors, and AT1 receptor blockers have been used, in singular or multiple blockade, to treat hypertension and other RAS-related diseases. High levels of Ang II are often related to hypertension, renal failure, and cardiac fibrosis.

in vitro

Most of the known actions of Angiotensin II (Ang II) are mediated by AT 1 receptors, the AT 2 receptor contributes to the regulation of blood pressure and renal function. Angiotensin II raises blood pressure (BP) by a number of actions, the most important ones being vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and renal actions. Other Angiotensin II actions include induction of growth, cell migration, and mitosis of vascular smooth muscle cells, increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis. These actions are mediated by type 1 Ang II receptors (AT 1 ). At the cellular level, responsiveness to Angiotensin II is conferred by the expression of the two classes of angiotensin receptors (AT 1 and AT 2 ). The effects of Angiotensin II to increase blood pressure are mediated by AT1 receptors.

in vivo

To distinguish the AT 1 receptor population that is critical for the pathogenesis of hypertension, osmotic minipumps are implanted s.c. into each animal to infuse Angiotensin II (1,000 ng/kg/min) continuously for 4 weeks. Angiotensin II causes hypertension by activating AT 1 receptors in the kidney promoting sodium reabsorption.

InChI:InChI=1/C50H71N13O12/c1-5-28(4)41(47(72)59-36(23-31-25-54-26-56-31)48(73)63-20-10-14-38(63)45(70)60-37(49(74)75)22-29-11-7-6-8-12-29)62-44(69)35(21-30-15-17-32(64)18-16-30)58-46(71)40(27(2)3)61-43(68)34(13-9-19-55-50(52)53)57-42(67)33(51)24-39(65)66/h6-8,11-12,15-18,25-28,33-38,40-41,64H,5,9-10,13-14,19-24,51H2,1-4H3,(H,54,56)(H,57,67)(H,58,71)(H,59,72)(H,60,70)(H,61,68)(H,62,69)(H,65,66)(H,74,75)(H4,52,53,55)/t28-,33-,34-,35-,36-,37-,38-,40-,41-/m0/s1

Upstream product

• 484-42-4 angiotensin I 
• 68858-20-8 Fmoc-Val-OH 
• 71989-14-5 Fmoc-(tBu)Asp-OH 
• 71989-38-3 Fmoc-Tyr(tBu)-OH 
• 71989-31-6 Fmoc-Pro-OH 
• 71989-23-6 Fmoc-Ile-OH 
• 109425-51-6 Fmoc-His(Trt)-OH 
• 15761-39-4 1-(tert-butoxycarbonyl)-L-proline 
• 13734-41-3 t-Boc-L-valine 
• 13139-16-7 N-(tert-butyloxycarbonyl)-L-isoleucine 
• 13836-37-8 Boc-Arg(Tos)-OH 
• 73821-95-1 Boc-Asp(O-cyclohexyl)-OH 
• 47689-67-8 (S)-3-[4-(2-Bromo-benzyloxycarbonyloxy)-phenyl]-2-tert-butoxycarbonylamino-propionic acid 
• 35899-43-5 Boc-His(Tos)-OH 

Downstream Products

• 1340585-05-8 C₆₅H₈₈F₃N₁₃O₁₈ 
• 1340585-06-9 C₈₄H₁₁₈F₃N₁₉O₂₃S 
• 1340585-07-0 C₈₄H₁₁₈F₃N₁₉O₂₃S 
• 85734-58-3 DOVYIHPF 

Relevant articles and documents

Comparative investigation of the cleavage step in the synthesis of model peptide resins: Implications for Nα-9- fluorenylmethyloxycarbonyl-solid phase peptide synthesis

Based on our studies of the stability of model peptide-resin linkage in acid media, we previously proposed a rule for resin selection and a final cleavage protocol applicable to the Nα-tert-butyloxycarbonyl (Boc)-peptide synthesis strategy. We found that incorrect choices resulted in decreases in the final synthesis yield, which is highly dependent on the peptide sequence, of as high as 30%. The present paper continues along this line of research but examines the Nα-9-fluorenylmethyloxycarbonyl (Fmoc)-synthesis strategy. The vasoactive peptide angiotensin II (AII, DRVYIHPF) and its [Gly 8]-AII analogue were selected as model peptide resins. Variations in parameters such as the type of spacer group (linker) between the peptide backbone and the resin, as well as in the final acid cleavage protocol, were evaluated. The same methodology employed for the Boc strategy was used in order to establish rules for selection of the most appropriate linker-resin conjugate or of the peptide cleavage method, depending on the sequence to be assembled. The results obtained after treatment with four cleavage solutions and with four types of linker groups indicate that, irrespective of the circumstance, it is not possible to achieve complete removal of the peptide chains from the resin. Moreover, the Phe-attaching peptide at the C-terminal yielded far less cleavage (50-60%) than that observed with the Gly-bearing sequences at the same position (70-90%). Lastly, the fastest cleavage occurred with reagent K acid treatment and when the peptide was attached to the Wang resin.

Resin selection based on the lability of peptidyl-resin linkage towards HF and TFA steps: Dependence on the C-terminal amino acid and peptide length

Ideally, the solid support used for tert-butyloxycarbonyl (Boc)-peptide synthesis method must allow sufficient stability of the peptide linkage towards TFA-α-amino deprotection but adequate lability to final HF cleavage. Due to these conflicting characteristics, the choice of the correct resin for peptide synthesis is complex and dependent upon many factors. Aiming to clarify this issue, a time-course study of the trifluoroacetic acid (TFA) and HF steps using model peptidyl-resins was developed. The peptidyl-resin bond stability was strongly dependent upon the resin and the carboxy-terminus residue. The decreasing order of acid stability for resins was: benzhydrylamine-resin (BHAR)>p-methylbenzhydrylamine-resin (MBHAR)?4- (oxymethyl)-phenylacetamidomethyl-resin (PAMR)>chloromethyl-resin (CMR) and Phe>Gly?His?Asp for C-terminal amino acids. HF-cleavage times of near 6 h (BHAR) and 23 h (MBHAR and PAMR) were necessary for quantitative cleavage of hydrophobic Phe residue-containing sequence at its C-terminal portion. When premature chain loss in TFA and incomplete cleavage in HF values were both quantitatively considered, a significant decrease in the overall yield (up to 35%) was observed in some resins. Moreover, MBHAR was more suitable than BHAR only when the peptide C-terminal residue is hydrophobic. The data also allow the prediction that due to more significant chain loss in TFA when MBHAR is used, BHAR will be the resin of choice for much longer than 40-mer peptide sequences containing C-terminal hydrophilic residues. Otherwise PAMR is the best resin for the synthesis of free carboxyl peptides but significantly low HF cleavage was observed when the C-terminal amino acid is of the hydrophobic-type.

Propargyl-Substituted Thiocarbamoylbenzamidines of Technetium and Rhenium: Steps towards Bioconjugation with Use of Click Chemistry

A new propargyl-substituted thiocarbamoylbenzamidine has been synthesized. The compound acts as a tetradentate ligand and forms stable complexes with {ReVO}3+and {TcVO}3+cores. Click couplings of the resulting complexes with benzylazide lead to prototype triazole derivatives, which were analyzed by NMR and IR spectroscopy and mass spectrometry, as well as by X-ray diffraction. A similar coupling procedure has been applied to an azido-modified angiotensin-II peptide, which gives the desired rhenium(V) bioconjugate in good yield. The ease of this coupling and the stability of the conjugate recommend such tetradentate thiocarbamoylbenzamidines also for clinically relevant bioconjugates with99mTc.

The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme

Enzyme-inhibitor recognition is considered one of the most fundamental aspects in the area of drug discovery. However, the molecular mechanism of this recognition process (induced fit or prebinding and adaptive selection among multiple conformers) in several cases remains unexplored. In order to shed light toward this step of the recognition process in the case of human angiotensin I converting enzyme (hACE) and its inhibitor captopril, we have established a novel combinatorial approach exploiting solution NMR, flexible docking calculations, mutagenesis, and enzymatic studies. We provide evidence that an equimolar ratio of the cis and trans states of captopril exists in solution and that the enzyme selects only the trans state of the inhibitor that presents architectural and stereoelectronic complementarity with its substrate binding groove.