58-82-2

Usage

Uses

1. Used in Cardiovascular Applications:
Bradykinin is used as a vasodilator for lowering blood pressure. It increases bradykinin levels by inhibiting its degradation, further lowering blood pressure. Bradykinin dilates blood vessels via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor.
2. Used in Pharmaceutical Research:
Leucine Enkephalin acetate salt hydrate, a derivative of bradykinin, has been used in the calibration of the Q-Tof Micro hybrid, triple quadrupole-orthogonal acceleration time of flight (TOF) instrument in single-stage TOF mode. It has also been used to perform the calibration of mass spectrometry and in liquid chromatography-mass spectrometry (LCMS)/MS for calibration of the system and for relative correction of the spectra.
3. Used in Pain Management:
Bradykinin is involved in the stimulation of pain receptors, making it a potential target for pain management research and development.
4. Used in Inflammation and Edema Research:
Bradykinin's role in mediating inflammation and edema resulting from trauma or injury makes it a relevant molecule for research in these areas.
5. Used in Post-Ischemic Heart Recovery:
Bradykinin's ability to improve post-ischemic recovery of the heart via a nitric oxide-dependent mechanism makes it a potential therapeutic target for heart-related conditions.
Chemical Properties:
Bradykinin is an amorphous solid.
Agonists and Antagonists:
[Lys0, des-Arg9]-BK is used as a B1 receptor agonist.
Cereport (RMP-7) is a selective B2 agonist, shown to transiently increase the permeability of the blood-brain barrier.
The B1 antagonist BI-113823 possesses an anti-inflammatory function.
Icatibant (HOE 140 or JE 049) is a potent, specific, and selective peptidomimetic B2 antagonist.

Receptors

BKs signal via two GPCRs known as the B1 (BDKRB1) and B2 (BDKRB2) receptors. These BK receptor genes were the result of tandem duplication that predated the teleost tetraploidization while no extra copy was found in teleosts. B2 is constitutively expressed and predominant in different tissues while B1 expression is induced by inflammation. B1 expression in inflammatory tissues such as a wound area and vascular injury contributes to the inflammatory edema by its vasodilatory effect on local blood vessels. B2 is ubiquitously expressed in different tissues. In the aorta and large muscular arteries, including the carotid and mesenteric arteries, B2 is localized predominantly in the endothelium. However, in small arterioles toward the urinary bladder, myometrium, breast, etc., B2 is located predominantly in the smooth muscle rather than the endothelium. bdkrb2- overexpressed zebrafish induce IP3 accumulation by BK with an EC50 of 6.6 nM.

Signal transduction pathway

Both B1 and B2 trigger a typical Ca signaling of GPCRs. Receptor activation leads to phospholipase C (PLC) activation, intracellular Ca mobilization, release of endothelium-dependent relaxation factor (EDRF), and activation of PKC and cytosolic PLA2 that results in the release of prostaglandins (PGs). The endothelial nitric oxide synthase (eNOS) is also stimulated by B2 activation, leading to an increase in NO, stimulation of guanylyl cyclase, and an increase in cGMP. Most of these factors are EDRFs and are contributing to the hypotensive effect of BK. However, in smooth muscle cells, B2 activation activates PLC directly, leading to a transient increase in Ca2+ flux to induce muscle contraction. Although BK mostly induces vasorelaxation via endothelium-dependent signalings, in small arterioles where B2 is predominately localized in the smooth muscle cells, BK induces vasoconstriction. In the light of this dual function, [Arg0 ]-BK injection in teleosts was a vasopressor and could be related to a direct stimulation of B2 on smooth muscles, as the endothelium-dependent relaxing system is not prominent in teleosts.

Biological Functions

The kallikrein–kinin system is an enzymatic pathway giving rise to two predominant vasoactive peptides, kallidin and bradykinin. Kallikrein, the enzyme responsible for the formation of these peptides, exists in plasma and tissues. However, circulating levels of the end products, kallidin and bradykinin, are quite low because the kallikrein enzymes are present largely in inactive forms. In addition, the short half-life of these peptides (15 seconds) also contributes to low plasma levels. In general, the kinins produce relaxation of vascular smooth muscle and vasodilation. Bradykinin causes vascular smooth muscle relaxation by stimulating the endothelium to release prostacyclin and nitric oxide. Blood flow to the brain, heart, viscera, skeletal muscle, and glands is increased. In nonvascular smooth muscle, bradykinin will produce a contractile response. Other actions of kinins include activation of clotting factors simultaneously with the production of bradykinin. In the kidney, bradykinin production results in an increase in renal papillary blood flow, with a secondary inhibition of sodium reabsorption in the distal tubule. In the peripheral nervous system, bradykinin is important for the initiation of pain signals. It is also associated with the edema, erythema, and fever of inflammation. Bradykinin exerts its physiological effects via two receptors, the B1 and B2 receptors, with most of its physiological effects being mediated by the B2 receptor. The precise function of the B1 receptor is unclear; however, some of the chronic inflammatory responses to bradykinin may be mediated through actions at this receptor. Bradykinin antagonists of the B2 receptor are currently in development and may find utility in the treatment of pain associated with burns and such chronic inflammatory disorders as arthritis, asthma, and chronic pain.

Hazard

Powerful vasodilator; increased capillary permeability; stimulates pain receptors; contraction of smooth muscle; teratogen; mutagenic.

Biochem/physiol Actions

Product does not compete with ATP.

Clinical Use

9-peptide, produced in response to tissue damage, inflammation, viral infections, etc. Produces pain, increased vascular permeability, and synthesis of prostaglandins.

InChI:InChI=1/C50H73N15O11/c51-32(16-7-21-56-49(52)53)45(72)65-25-11-20-39(65)47(74)64-24-9-18-37(64)43(70)58-28-40(67)59-34(26-30-12-3-1-4-13-30)41(68)62-36(29-66)46(73)63-23-10-19-38(63)44(71)61-35(27-31-14-5-2-6-15-31)42(69)60-33(48(75)76)17-8-22-57-50(54)55/h1-6,12-15,32-39,66H,7-11,16-29,51H2,(H,58,70)(H,59,67)(H,60,69)(H,61,71)(H,62,68)(H,75,76)(H4,52,53,56)(H4,54,55,57)/t32-,33-,34-,35-,36-,37-,38-,39-/m0/s1

Upstream product

• 71989-31-6 Fmoc-Pro-OH 
• 35661-40-6 N-Fmoc L-Phe 
• 73724-45-5 N-(9H-fluoren-9-ylmethoxycarbonyl)-L-serine 
• 91000-69-0 Fmoc-L-Arg-OH 
• 4530-20-5 BOC-glycine 
• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 13726-76-6 t-butyloxycarbonyl-L-arginine 
• 78545-07-0 (S)-3-(benzoyloxy)-2-((tert-butoxycarbonyl)amino)propanoic acid 
• 16875-08-4 L-Ser-L-Pro-L-Phe-L-Arg 
• 23815-89-6 Bradykinin (1-5) 
• 29022-11-5 N-(fluoren-9-ylmethoxycarbonyl)glycine 

Downstream Products

• 83100-50-9 C₆₂H₈₆Cl₂N₁₆O₁₂ 
• 56-45-1 L-serin 

Relevant academic research and scientific papers

Peptide dissociation in solution or bound to a polymer: Comparative solvent effect

Dissociation of peptide when in solution or attached to a polymer was investigated. Magnified solvation of peptide-resins occurred in solvent with similar polarity. Conversely the solubilization of peptides was not usually directly related to the medium polarity. The greater the difference between acidity and basicity of solvent and its potential to form van der Waals interaction, the stronger its solubilization strength. Solvents with similar electrophilicity and nucleophilicity usually did not solvate aggregated peptide-resins nor dissolve peptides. The peptide solubilization in water-containing mixed solvents depended on combination of acidity/basicity of both components. Some criteria for choosing suitable solvents for peptide-resin solvation or peptide solubilization could be advanced. Graphical abstract.

Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord

We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg10, Leu9]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure-activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg7]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn As biological activity, is not necessary, and that a type I B-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using na?ve rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.

Substrate specificity studies of the cysteine peptidases falcipain-2 and falcipain-3 from Plasmodium falciparum and demonstration of their kininogenase activity

We studied the substrate specificity requirements of recombinant cysteine peptidases from Plasmodium falciparum, falcipain-2 (FP-2) and falcipain-3 (FP-3), using fluorescence resonance energy transfer (FRET) peptides as substrates. Systematic modifications were introduced in the lead sequence Abz-KLRSSKQ-EDDnp (Abz = ortho-aminobenzoic acid; EDDnp = N-[2,4-dinitrophenyl] ethylenediamine) resulting in five series assayed to map S3-S ′2 subsite specificity. Despite high sequence identity and structural similarity between FP-2 and FP-3, noteworthy differences in substrate specificity were observed. The S1 subsite of FP-2 preferentially accommodates peptides containing the positively charged residue Arg in P 1, while FP-3 has a clear preference for the hydrophobic residue Leu in this position. The S2 subsite of FP-2 and FP-3 presents a strict specificity for hydrophobic residues, with Leu being the residue preferred by both enzymes. FP-2 did not show preference for the residues present at P 3, while FP-3 hydrolysed the peptide Abz-ALRSSRQ-EDDnp, containing Ala at P3, with the highest catalytic efficiency of all series studied. FP-2 has high susceptibility for substrates containing hydrophobic residues in P′1, while FP-3 accommodates well peptides containing Arg in this position. The S′2 subsite of both enzymes demonstrated broad specificity. In addition, radioimmunoassay experiments indicated that kinins can be generated by FP-2 and FP-3 proteolysis of high molecular weight kininogen (HK). Both enzymes excised Met-Lys-bradykinin, Lys-bradykinin and bradykinin from the fluorogenic peptide Abz-MISLMKRPPGFSPFRSSRI-NH2, which corresponds to the Met 375 to Ile393 sequence of HK. The capability of FP-2 and FP-3 to release kinins suggests the involvement of these enzymes in the modulation of malaria pathophysiology.

Controlled formation of peptide bonds in the gas phase

Photoexcitation (using 157 nm vacuum ultraviolet radiation) of proton-bound peptide complexes leads to water elimination and the formation of longer amino acid chains. Thus, it appears that proton-bound dimers are long-lived intermediates along the pathway to peptide formation. Product specificity can be controlled by selection of specific complexes and the incorporation of blocking groups at the N- or C-termini. The product peptide sequences are confirmed using collision-induced dissociation.

New phototriggers 9: p-Hydroxyphenacyl as a C-terminal photoremovable protecting group for oligopeptides

In our search for a more versatile protecting group that would exhibit fast release rates for peptides, we have designed and developed the p- hydroxyphenacyl (pHP) group as a new photoremovable protecting group. We report the application of this protecting group for the dipeptide Ala-Ala (1) and for the nonapeptide bradykinin (2), two representative peptides that demonstrate C-terminus 'caging' and photorelease. The synthesis of these p- hydroxyphenacyl esters was accomplished in good yields by DBU-catalyzed displacement of bromide from p-hydroxyphenacyl bromide. As in the case of caged γ-amino acids 11 (pHP glu) and 12 (pHP GABA) and caged nucleotide 17 (pHP ATP) reported earlier, irradiations of the p-hydroxyphenacyl esters of 1 and 2 actuate the release of the peptides with rate constants that are consistently greater than 108 s-1 and appearance efficiencies (Φ(app)) that range from 0.1 to 0.3. Release of the substrate is accompanied by a deep-seated rearrangement of the protecting group into the near-UV silent p- hydroxyphenylacetic acid (6). Quenching studies of pHP Ala-Ala (7) with either sodium 2-naphthalenesulfonate or potassium sorbate gave good Stern- Volmer kinetics yielding a rate constant for release of 1.82 x 108 s-1. Quenching of the phosphorescence emission from pHP Ala-Ala (7, E(T) = 70.1 kcal/mol) and pHP GABA (12, E(T) = 68.9 kcal/mol) were also observed. The biological efficacy of bradykinin released from pHP bradykinin (9) was examined on single rat sensory neurons grown in tissue culture. A single 337 nm flash (1 ns) released sufficient bradykinin from the p-hydroxyphenacyl protected nonapeptide to activate cell-surface bradykinin receptors as indicated by a rapid increase in the intracellular calcium concentration. A selective antagonist of type 2 bradykinin receptors blocked the biological response. From these results, it is apparent that flash photolysis of p- hydroxyphenacyl protected peptides provides a powerful tool for the rapid and localized activation of biological receptors.

The solid phase synthesis of peptides containing an arginine residue with an unprotected guanidine group

A new variant of the solid phase synthesis of arginine-containing peptides was proposed. The conditions for the attachment to the Wang polymer of Nα-Fmoc-arginine containing a protonated guanidine group were found. We demonstrated that this attachment is accompanied by neither racemization nor the attachment of the second Arg residue. Side reactions involving the guanidine group of arginine were studied, and methods for their prevention were proposed. The comparison of the carbodiimide method with a 1-hydroxybenzotriazole additive and a modified method with the use of Kastro's reagent for the introduction of Nα-Fmoc-Arg residue with the unprotected guanidine group into the growing peptide chain demonstrated the advantages of the second method. Bradykinin and a peptide corresponding to the 584-591 sequence of the transmembrane gp41 from HIV-1 were synthesized by the method proposed here.

Cytolytic bradykinin antagonists

The present invention provides bradykinin antagonists effective to inhibit cancer cell growth. Also provided are methods of inhibiting lung cancer cell growth by administering a therapeutically effective amount of a dimerized bradykinin antagonist.

Le chloroformiate d'isopropenyle (IPCF) en chimie des peptides. II. Application a la synthese d'oligopeptides preparations de la tuftsine et de la bradykinine

Isopropenyl chloroformate has been proved to be very suitable for dipeptides synthesis (1).We have extended the field of application of this reagent to the oligopeptides synthesis for mixed-anhydride method at ambient temperature.Interesting results were obtained in the preparation of tuftsin and bradykinin.