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Bradykinin Receptor Antagonist Pdf Free HOT!


Bradykinin (BK) (Table 1) belongs to the kinin protein group and influences a wide range of physiological responses via two metabotropic G protein-coupled receptors (GPCRs) known as B1 (B1R) and B2 (B2R). B2Rs are constitutively expressed in most cell types, whereas B1Rs are present only in tissue inflammation1. Activation of B2R causes slow, sustained smooth muscle contraction, alteration of epithelial cell ion secretion, increased vascular permeability, increased mucosal secretion, release of cytokines from leukocytes, stimulation of sensory neurons, and production of eicosanoids from a variety of cell types2,3. BK has been linked with a variety of diseases, including chronic pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and several other inflammatory diseases. BK is also considered a growth factor involved in the development and progression of cancer4. However, the mechanism of the tumor growth-promoting effect of this kinin is still unknown. GPCRs can be blocked by GPCR antagonists, which effectively compete with native peptides. Therefore, GPCR antagonists are an effective chemotherapeutic and diagnostic strategy in drug development5,6. In this context, several studies continue to focus on the development of mutant analogs that have both much higher affinity and antagonistic properties and weaker agonistic properties of these receptors. Because of these properties, specifically modified analogs can effectively compete with the native peptide; when they bind preferentially to GPCRs, they block these receptors from acting. Since clinical studies have shown that the main actions of BK are B2R functions, most attempts to synthesize effective BK antagonists have focused on analogs known as B2 bradykinin antagonists7,8. The search for B1R antagonists is also important because B1Rs are potential targets for drug development in pain processes9.




Bradykinin Receptor Antagonist Pdf Free


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Despite the great interest in BK and its antagonists, which are selective for a single receptor class and represent an extremely important tool for elucidating the physiological and pathological roles played by naturally occurring peptides and their receptors, there is still a great need for research on BK analogs with antagonistic properties. The studies presented in this paper are an integral part of this scientific problem and are devoted to several analogs of BK (Table 1) and the determination of their biological activity using cell lines overexpressing B1R and B2R, as well as the intracellular inositol monophosphate (IP1) assay.


The studies presented here also describe peptide structures and adsorption changes resulting from modifying the peptide chain. These issues need to be addressed to better understand the interaction mechanism between BK and the receptors and are critical for the development of new BK antagonists with increased affinity for the receptors. Surface-enhanced Raman scattering (SERS) has shown promise in structural-activity studies to predict the biochemical activity of some neuropeptides19,20,21. For example, SERS has been used to determine the adsorbed molecular structures and the changes in these structures and adsorption resulting from substitution of natural amino acids by synthetic amino acids of bombesin (BN) and its analogs deposited on the Ag surface19. In the BN fragments, the relative efficacy of inhibiting the binding of 125I-[Tyr4]BN to rat pancreatic acini cells was correlated with the behavior of the amide binding on the Ag surface, whereas the contribution of structural components to the ability to interact with the GPCR was correlated with the SERS patterns. In other words, SERS enabled the identification of important amino acid residues involved in substrate-receptor interactions in systems where biological studies are difficult or do not clearly identify the molecular fragments responsible for the biological activity of the peptide.


Influence of BK on IP1 levels in the mock T-REx 293 cell line. There is no functional activity of a BK receptor in this cell line because it is not expressed (A) and the effect of BK on T-REx 293 cells expressing B1R (B) or B2R (C). A dose-dependent increase in intracellular IP1 level was observed in presence of BK. In addition, specific antagonist activity for B1R and B2R was examined in the presence of BK, corresponding to EC80 for each receptor (12.5 µM for B1R and 25 nM for B2R).


Eleven derivatives of BK were analyzed in the screening procedure using both cell lines. The compounds were administered alone or in the presence of BK, corresponding to the EC80 of the antagonist (Fig. 2). For B1R, compounds BK1 and BK2 showed agonistic activity alone (Fig. 2A). Compounds BK5/6/8 and BK9 were neutral to receptor activity but did not abolish bradykinin action. An antagonistic effect in the presence of BK was observed for compounds BK3/4/7/10 and BK11.


In further experiments, the U87-MG, SHP-77, and H4 cell lines were used for the functional assay with BK and the reference B1R antagonist. As shown in Fig. 13S in Supplementary File, all three cell lines expressed the functional B1R protein and its activity according to the mRNA level shown in Fig. 4. The obtained results are consistent with previous findings showing the expression of functional B1R and B2R genes and proteins in human glioblastoma cells U87-MG32,33. In other studies, cellular expression of B1 and B2 receptors was detected in five different subtypes of human lung carcinomas (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, and carcinoid tumors)34. In addition, B2R has also been characterized in the cell line SHP-7735. However, to our knowledge, this is the first time that we have detected B1R and B2R gene expression in H4 cells of human brain neuroglioma and B1R in SHP-77 cells of human lung carcinoma. Interestingly, both U87-MG and H4 cell lines expressed higher levels of B1R mRNA compared with B2R, which could be explained by the inducible property of B1R under abnormal conditions, such as cancer36.


All five antagonists were immobilized at the AuNPs/liquid interface, and adsorption was monitored using SERS. The SERS spectra were analyzed in terms of the vibrations of these molecular fragments (amino acid side chains) responsible for the biological activity. Analysis of the SERS spectra shows that the combination of modifications at the D-Pip7 and Thi8 positions with Aaa0' (the analog BK11) leads to a skeletal structure in which the piperidine ring adopts an end-on orientation with respect to the surface of the AuNPs. At this orientation, the nitrogen free electron pair is directed toward this surface, and the thiophene ring, whose free electron pair interacts only weakly with the AuNPs, assumes a nearly horizontal position relative to this surface. None of the other bradykinin analogs studied exhibits such an adsorbed structure, suggesting that the specific interaction between D-Pip7 and Thi8 and B1R, as well as the AuNP surface, may be responsible for the antagonistic properties of BK11.


We further assessed engagement through B1R of sCD13-induced signaling molecules. The results reinforce our previous data suggesting that sCD13 has a direct effect in increasing the phosphorylation of signaling molecules such as Erk1/2 in RA FLSs. Roles of DABK and B1R are well described in phosphorylation of mitogen-activated protein kinase (MAPK) (31, 32). In our current work, a B1R antagonist significantly inhibited both sCD13-induced and DABK-induced phosphorylation of signaling molecules, further verifying that B1R has more than one ligand. In RA FLSs transfected with B1R-silencing RNA, sCD13-stimulated Erk1/2 phosphorylation was markedly decreased in comparison with scrambled RNA, thus confirming that B1R is a receptor for sCD13.


In this study, we showed that sCD13, acting through B1R, is emerging as a potent, pleiotropic mediator in the pathogenesis of inflammatory arthritis. B1R appears to mediate all of the proinflammatory effects of sCD13, notably including the secretion of inflammatory cytokines from ex vivo RA ST organ cultures. Considering the RA ST organ culture as an established RA disease model, besides B1R blockade, we have not encountered other interventions that show efficacy similar to that of the positive control dexamethasone. In addition, B1R antagonists inhibit development of arthritis and joint destruction in animal models. Targeting B1R, the sCD13 receptor, may provide an effective approach to treating chronic inflammatory diseases such as RA because sCD13 modulates the functions of almost all cell types involved in RA pathogenesis. Thus sCD13 and its receptor provide therapeutic targets for RA, and potentially a broader range of immune-mediated diseases.


The Kallikrein-Kinin System (KKS) has been found to play a role in tumor progression in several cancers. The KKS metabolic cascade depends on signalling through two cross talking receptors; bradykinin receptor 1 (B1R) and bradykinin receptor 2 (B2R). Activation of the Kinin receptor is responsible for multiple pathophysiologic functions including increase of vascular permeability and induction of host inflammatory responses that exert diverse effects on tumor growth.


We first wanted to establish whether our CRC cell lines (MoCR and SW480) express B1R and/or B2R. Immunohistochemical staining for these receptors confirmed their expression (Additional file 1), supporting previous published studies that CRC cells express bradykinin receptors [22].


Here we show that kinin receptors are involved in MoCR tumor progression In an in vivo CRLM mouse model tumor angiogenesis is inhibited and tumor progression retarded by B1R and B2R blockade. In addition, B1R inhibition led to significant reduction in the percentage of live tumor, possibly due to the increased tumor apoptosis. In an in vitro setting B1R and B2R antagonists decreased both tumor proliferation and migration. Taken together the results indicate that KKS manipulation could be a novel therapeutic target for treatment of colorectal cancer.


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