Trends in Pharmacological Sciences
ViewpointB1 receptors as a new inflammatory target. Could this B the 1?
Section snippets
Induction of B1 receptors: how, where and when
The biological effects of BK are brought about by its interaction with specific G protein-coupled receptors4, 5. At present, there are two clearly defined and cloned kinin receptors: B1 and B2. B2 receptors are constitutively present on many cell types involved with the inflammatory response: endothelial cells, mast cells3 and sensory neurones6. The natural endogenous ligand for this receptor is BK, with Lys-BK in most cases possessing a lower afffinity for the receptor. In contrast, B1
Relevance of B1 receptors to inflammation
It is now clear that responses to DABK are, in the large part, observed following a pathological insult, and experimentally this has been very well demonstrated using models of sepsis and nociceptive inflammation24. In both cases, a rise in local or circulating cytokine levels, particularly interleukin 1 (IL-1), has been implicated in the process of induction. There is support for the concept that not only are B1 receptors upregulated by specific inflammatory stimuli, but that there is also an
Concluding remarks
The picture emerging from several recent studies is that the physiological tonic actions of kinins involve activation of B2 receptors. However, in pathological conditions, it is not only B2 receptors that mediate the inflammatory actions of kinins: B1 receptors are induced de novo and might be activated by the specific endogenous agonist DABK, which is elevated in inflammatory exudates. In the inflammatory scenario, the effects of B1 receptor activation are often qualitatively similar to those
Acknowledgements
AA is supported by the British Heart foundation and MP by the Arthritis Rheumatism Council.
Glossary
Chemical names
- BN9958:
- Lys-Lys-[Hyp3,Cpg5,D-Tic7,Cpg8]desArg9BK
- FR173657:
- (E)-3-(6-acetamido-3-pyridyl)-N-(N-[2,4-dichloro-3{(2-methyl-8-quinolinyl)oxymethyl}phenyl]-N-methylaminocarbonyl-methyl)acrylamide
- Hoe140:
- [d-Arg-Arg-Pro-Hyp-Gly-(β-2-thienyl)-Ala-Ser-dTic-Oic-Arg
- WIN64338:
- [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2-naphthyl)-1-oxopropyl]amino]phenyl]methyl]tributyl phosphonium chloride monohydrochloride
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The relevance of kalikrein-kinin system via activation of B<inf>2</inf> receptor in LPS-induced fever in rats
2017, NeuropharmacologyCitation Excerpt :Such results suggest the involvement of both receptors in the pyrogenic effect of BK when animals have been previously treated with captopril. Indirect evidence suggests that activation of B2 kinin receptors promotes induction of B1 kinin receptor expression (Ahluwalia and Perretti, 1999; Calixto et al., 2000). The proposed mechanisms to the induction of B1 receptors involve stimulation of inflammatory cells with production of inflammatory mediators.
New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding
2016, Journal of Molecular Graphics and ModellingCitation Excerpt :Most attempts in the past were devoted to develop antagonists of the B2 receptor [4], with a stride made after the market release of the peptide antagonist Icatibant [5,6]. More recently, the demonstrated implication of B1 in establishing and maintaining the signaling of chronic and inflammatory pain [3,7,8], as well as in hyperalgesia and leucocyte infiltration through the activation of a cytokine network, has increased the interest in finding small molecule B1 antagonists for the treatment of both pain and inflammation [9–13]. Despite of these efforts there is no drug currently in the market designed to antagonize the B1 bradykinin receptor.
Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency
2012, Bioorganic and Medicinal Chemistry LettersModulation of retinal blood flow by kinin B<inf>1</inf> receptor in Streptozotocin-diabetic rats
2011, Experimental Eye ResearchCitation Excerpt :Through the activation of two G-protein coupled receptors, named B1 (B1R) and B2 (B2R) (Regoli and Barabe, 1980; Regoli et al., 1998), these inflammatory peptides mediate enhanced capillary permeability, edema, leukocytes infiltration, vasodilation and regulation of local blood flow (Couture et al., 2001; Marceau et al., 1998). The activation of either receptor induces release of nitric oxide (NO) and prostaglandins (PGs) from vascular endothelial cells which consequently promote vasodilation (Ahluwalia and Perretti, 1999; McLean et al., 1999). The widely distributed B2R mediates the acute effects of bradykinin (BK) and kallidin (KD).
3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation
2011, Bioorganic and Medicinal Chemistry Letters