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(Hyp3,β-(2-thienyl)-Ala5,Tyr(Me)8-(R)-Arg9)-Bradykinin是一种选择性缓激肽B2受体激动剂，其血浆半衰期比缓激肽长，并短暂增加血脑屏障（BBB）通透性，促进药物向中枢神经系统的递送。

(Hyp3,β-(2-thienyl)-Ala5,Tyr(Me)8-(R)-Arg9)-Bradykinin, a selective bradykinin B2 receptor agonist, has a longer plasma half-life than bradykinin, and transiently increases the blood-brain barrier (BBB) permeability to facilitate drug delivery to the central nervous system.

Bradykinin is a peptide hormone that is produced in the body and has various physiological effects, such as vasodilation, bronchoconstriction, and the release of histamine from mast cells. Bradykinin is also used in pharmacological treatments for malignant brain tumors, congestive heart failure, and epidermal growth factor-responsive dermatoses. Bradykinin can be administered intravenously or subcutaneously to treat these conditions. The drug can also be administered intraperitoneally to treat high blood pressure during pregnancy. Bradykinin is an ester of 3-b-(2-thienyl)-Ala5,Tyr(Me)8-psi(CH2NH)Arg9-OH with trifluoroacetic acid. It is synthesized by linking two molecules together through an ester bond. This drug has many beneficial effects on the human body due to its ability to inhibit enzymes that are involved in the production of prostagland

(Hyp³,β‑(2‑噻吩基)‑Ala⁵,Tyr (Me)⁸,(R)‑Arg⁹)‑缓激肽是缓激肽类似物，含独特取代基，包括羟基化脯氨酸与噻吩基丙氨酸。这些修饰增强稳定性与受体相互作用，适用于研究炎症与血管舒张中缓激肽受体介导效应。该化合物用于心血管研究与炎症反应调节研究。

(Hyp3,beta-(2-thienyl)-Ala5,Tyr(Me)8,(R)-Arg9)-Bradykinin is a bradykinin analog with unique substitutions, including hydroxylated proline and thienylalanine. These modifications enhance its stability and receptor interaction, making it useful for studying bradykinin receptor-mediated effects in inflammation and vasodilation. This compound is utilized in cardiovascular research and inflammatory response modulation studies.

Definition

Bradykinin is a nonapeptide that is mainly found in animal preparations that are treated with the venom of the snake, Bothrops jararaca1,2.  It dialates blood vessels that in turn leads to decrease in blood pressure2. Bradykinin analogs are slightly modified structural derivatives of bradykinin that perform similar functions as bradykinin3.

Discovery

Bradykinin was discovered in the blood plasma of animals that were treated with the venom from the Brazilian snake, Bothrops jararaca1,2.  The discovery was part of a study that was related to toxicology of snake bites.  Bradykinin analogs were synthesized by solid-phase techniques in 1975 and their function was studied in rats and rabbits3.

Classification

Bradykinin is a 9 amino acid peptide that belongs to the kinin family of proteins4.  It has homologs in several animals including other snakes, frog, dog and humans4.

Structural Characteristics

Bradykinin has the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg3.  Several analogs of bradykinin have been synthesized. They are also nanopeptides containing substitutions of various amino acids of bradykinin. For example two analogs of bradykinin were synthesized one with 7-beta-homo-L-proline and the other with 8-beta-homo-L-phenylalanine substitutions3.  It was found that both of them are resistant to enzymatic degradation3.

Mode of action

Bradykinin binds to two different kinin G protein coupled receptors- B1 and B25.  Upon binding to these receptors it induces conversion of GTP to GDP which in turn triggers the conversion ATP to cAM which then acts as a second messenger resulting in the activation of genes.  B1 receptor is expressed as a result of tissue injury and is found to play a role in inflammation while B2 receptor participates in the vasodilatory role of bradykinin5,6.  Bradykinin analogs function is a similar fashion although depending on their structure they might have varying affinities to the receptors compared to bradykinin7. Also analogs of bradykinin have been synthesized that are specific to one of these receptors7.

Functions

Bradykinin is a potent endothelium-dependent vasodilator, causes contraction of non-vascular smooth muscle, increases vascular permeability and also is involved in the mechanism of pain. Bradykinin also causes natriuresis, contributing to a drop in blood pressure8. Bradykinin raises internal calcium levels in neocortical astrocytes causing them to release glutamate9. Overactivation of bradykinin is thought to play a role in a rare disease called Hereditary Angioedema, also known as Hereditary Angio-Neurotic Edema10. 

Some analogs of bradykinin have been found to have prolonged hypotensive action compared to bradykinin (Eg: beta-H-Pro-bradykinin)3.  Some analogs have relative or even lower potencies compared to bradykinin (Eg: HArg1-Bradykinin and HArg9 Bradykinin)7.  Other analogs have been studied for their potential of finding bradykinin antagonists that might be useful in the treatment of angio-neurotic edema.  

References

1.     Partridge, SM (1948). (Title or abstract not available), Biochem. J., 42, 238.

2.     Allen PK, Kusumam J, Yoji S, Yoshitaka N, Berhane G, Sesha R and Michael S (1998). Bradykinin formation: Plasma and tissue pathways and cellular interactions. Clinical reviews in allergy and immunology, 16, 4, 403-429.

3.     Ondetti MA, Engel SL (1975). Bradykinin analogs containing beta.-homoamino acid, J. Med. Chem.,18 (7), 761–763.

4.     Roseli A, Gomes S, Jair RC, Luis J and Valdemar H (1996). Met-Lys-Bradykinin-Ser, the kinin released from human kininogen by human pepsin. Immunopharmacology, 32, 76-79.

5.    Peter GM, Amrita A, and Mauro P (2000). Association between Kinin B1 Receptor Expression and Leukocyte Trafficking across Mouse Mesenteric Postcapillary Venules. J Exp. Med., 192, 367-380.

6.     Duchene J, Lecomte F, Ahmed S, Cayla C, Pesquero J, Bader M, Perretti M and Ahluwalia A, (2007). A Novel Inflammatory Pathway Involved in Leukocyte Recruitment: Role for the Kinin B1 Receptor and the Chemokine CXCL5. J Immunol., 179, 4849-4856.

7.     Max ES, Phyllis AL (1974). Synthesis and pharmacology of homoarginine bradykinin analog. J. Med. Chem., 17 (11), pp 1227–1228.

8.     Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P, (2001). Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol., 280:H2182

9.     Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (2000). Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma. Am J Physiol Heart Circ Physiol, 278(4):H1069-74.

10.   Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (2007). Nonallergic angioedema: role of bradykinin. Allergy, 62(8):842-56.