B1 receptors as a new inflammatory target. Could this B the 1?

doi:10.1016/S0165-6147(99)01321-8

Trends in Pharmacological Sciences

Volume 20, Issue 3, 1 March 1999, Pages 100-104

https://doi.org/10.1016/S0165-6147(99)01321-8 Get rights and content

Abstract

The kinins, particularly bradykinin (BK), are important mediators involved in both the initiation and progression of an inflammatory response. The pro-inflammatory effects of kinins are mediated by at least two receptors: the B₂ subtype is expressed constitutively and the B₁ receptor is induced following tissue inflammation and damage. The endogenous ligand for the B₁ receptor is des-arg⁹BK, a cleavage product of the activity of carboxypeptidases on BK. Activation of B₁ receptors produces a range of pro-inflammatory effects including oedema, pain and promotion of blood-borne leukocyte trafficking. In this article Amrita Ahluwalia and Mauro Perretti briefly describe the biology of BK and its receptors, and discuss the possible development of B₁ receptor antagonists as novel anti-inflammatory agents.

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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Chemical composition and evaluation of the anti-inflammatory and antinociceptive activities of Duguetia furfuracea essential oil: Effect on edema, leukocyte recruitment, tumor necrosis factor alpha production, iNOS expression, and adenosinergic and opioidergic systems
2019, Journal of Ethnopharmacology
Citation Excerpt :
This situation has led to a search for bioactive natural products, setting the plant species as a valuable source (Barreiro and Bolzani, 2009; Carneiro et al., 2014). The inflammatory process consists of the highly complex interplay between various factors at the humoral and cellular levels (Ahluwalia and Perretti, 1999). The in vivo LPS model is of great clinical relevance and has been used as an approach to inflammation induced by gram-negative bacteria infection (Cunha et al., 2005; Endale et al., 2013).
Duguetia furfuracea (A. St. -Hil.) Saff. (Annonaceae) is commonly known in Brazil as “araticum-seco,” and its root is used in folk medicine to treat inflammatory and painful disorders. However, no studies have been performed to evaluate these therapeutic activities.
Investigate the chemical composition, anti-inflammatory and antinociceptive effects, and elucidate the possible antinociceptive mechanisms of action from the essential oil of D. furfuracea (EODf) underground stem bark.
Chemical composition was determined by gas chromatography and mass spectrometry (GC/MS). The paw edema induced by LPS, formalin-induced nociception, LPS-induced thermal hyperalgesia and rota-rod tests in vivo were used to evaluate the anti-inflammatory and antinociceptive effects in addition to the alteration on motor coordination. Histological analyses and an immunohistochemistry assay for iNOS were performed on mouse footpads of naive, control, 10 mg/kg EODf, and 10 mg/kg indomethacin (Ind) groups. The samples were removed at 1, 3, and 6 h after subplantar injection of LPS. In addition, the involvement of the adenosinergic, opioidergic, serotonergic, and cholinergic systems were investigated, in order to elucidate possible antinociceptive mechanisms.
Twenty-four volatile constituents were detected and identified. (E)-asarone (21.9%), bicyclogermacrene (16.7%), 2,4,5-trimethoxystyrene (16.1%), α-gurjunene (15%), cyperene (7.8%), and (E)-caryophyllene (4.6%) were major compounds found in EODf. Oral treatment (p.o.) with EODf (1, 3, and 10 mg/kg) significantly inhibited the paw edema induced by LPS. At 10 mg/kg EODf promoted inhibition of tumor necrosis factor alpha (TNF-α) production, recruitment of polymorphonuclear (PMN) leukocytes and inducible nitric oxide synthase (iNOS) expression in paw tissue. EODf (10 and 30 mg/kg, p.o.) also reduced licking time in both phases of the formalin test and it had a significant effect on the LPS-induced thermal hyperalgesia model. The administration of caffeine (Caf) and naloxone (Nal) reversed the antinociceptive activity of EODf, in the first phase of the formalin test and in the LPS-induced thermal hyperalgesia model. Moreover, Nal was also able to abolish the antinociception caused by EODf, in the second phase of formalin test. In the rota-rod test, EODf-treated animals did not show any alteration of motor coordination.
Our findings indicate that EODf underground stem bark produces anti-inflammatory and both central and peripheral antinociceptive effects. Furthermore, the antinociceptive activity of EODf underground stem bark is possibly mediated by adenosinergic and opioidergic pathways, and its properties do not induce effects on motor coordination. These results support the use of the folk medicine, D. furfuracea root, to treat inflammation and painful conditions.
The relevance of kalikrein-kinin system via activation of B<inf>2</inf> receptor in LPS-induced fever in rats
2017, Neuropharmacology
Citation 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.
This study evaluated the involvement of endogenous kallikrein-kinin system and the bradykinin (BK) B₁ and B₂ receptors on LPS- induced fever and the POA cells involved in this response.
Male Wistar rats received either i.v. (1 mg/kg), i.c.v. (20 nmol) or i.h. (2 nmol) injections of icatibant (B₂ receptor antagonist) 30 or 60 min, respectively, before the stimuli. DALBK (B₁ receptor antagonist) was given either 15min before BK (i.c.v.) or 30 min before LPS (i.v.). Captopril (5 mg/kg, sc.,) was given 1 h prior LPS or BK. Concentrations of BK and total kininogenon CSF, plasma and tissue kallikrein were evaluated. Rectal temperatures (rT) were assessed by telethermometry. Ca⁺⁺ signaling in POA cells was performed in rat pup brain tissue microcultures.
Icatibant reduced LPS fever while, captopril exacerbated that response, an effect abolished by icatibant. Icatibant (i.h.) reduced fever to BK (i.h.) but not that induced by LPS (i.v.). BK increased intracellular calcium concentration in neurons and astrocytes. LPS increased levels of bradykinin, tissue kallikrein and total kininogen. BK (i.c.v.) increased rT and decreased tail skin temperature. Captopril potentiated BK-induced fever an effect abolished by icatibant. DALBK reduced the fever induced by BK. BK (i.c.v.) increased the CSF PGE₂concentration. Effect abolished by indomethacin (i.p.).
LPS activates endogenous kalikrein-kinin system leading to production of BK, which by acting on B₂-receptors of POA cells causes prostaglandin synthesis that in turn produces fever. Thus, a kinin B₂-receptor antagonist that enters into the brain could constitute a new and interesting strategy to treat fever.
New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding
2016, Journal of Molecular Graphics and Modelling
Citation 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.
Bradykinin (BK) is a nonapeptide involved in several pathophysiological conditions including among others, septic and haemorrhagic shock, anaphylaxis, arthritis, rhinitis, asthma, inflammatory bowel disease. Accordingly, BK antagonists have long been sought after for therapeutic intervention. Action of BK is mediated through two different G-protein coupled receptors known as B1 and B2. Although there are several B1 antagonists reported in literature, their pharmacological profile is not yet optimal so that new molecules need to be discovered. In the present work we have constructed an atomistic model of the B1 receptor and docked diverse available non-peptide antagonists in order to get a deeper insight into the structure-activity relationships involving binding to this receptor. The model was constructed by homology modeling using the chemokine CXC4 and bovine rhodopsin receptors as template. The model was further refined using molecular dynamics for 600 ns with the protein embedded in a POPC bilayer. From the refinement process we obtained an average structure that was used for docking studies using the Glide software. Antagonists selected for the docking studies include Compound 11, Compound 12, Chroman28, SSR240612, NPV-SAA164 and PS020990. The results of the docking study underline the role of specific receptor residues in ligand binding. The results of this study permitted to define a pharmacophore that describes the stereochemical requirements of antagonist binding, and can be used for the discovery of new compounds.
Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency
2012, Bioorganic and Medicinal Chemistry Letters
Modulation of retinal blood flow by kinin B<inf>1</inf> receptor in Streptozotocin-diabetic rats
2011, Experimental Eye Research
Citation 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).
The vasoactive kinin B₁ receptor (B₁R) is overexpressed in the retina of diabetic rats in response to hyperglycemia and oxidative stress. The aim of the present study was to determine whether B₁R could contribute to the early retinal blood flow changes occurring in diabetes. Male Wistar rats were rendered diabetic with a single i.p. injection of Streptozotocin (STZ) and studied 4 days or 6 weeks after diabetes induction. The presence of B₁R in the retina was confirmed by Western blot. The impact of oral administration of the B₁R selective antagonist SSR240612 (10 mg/kg) was measured on alteration of retinal perfusion in awake diabetic rats by quantitative autoradiography. Data showed that B₁R was upregulated in the STZ-diabetic retina at 4 days and 6 weeks. Retinal blood flow was not altered in 4-day diabetic rats compared with age-matched controls but was significantly decreased following SSR240612 treatment. In 6-week diabetic rats, retinal blood flow was markedly reduced compared to control rats and SSR240612 did not further decrease the blood flow. These results suggest that B₁R is upregulated in STZ-diabetic retina and has a protective compensatory role on retinal microcirculation at 4 days but not at 6 weeks following diabetes induction.
3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation
2011, Bioorganic and Medicinal Chemistry Letters
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC₅₀ of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.

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Trends in Pharmacological Sciences

ViewpointB1 receptors as a new inflammatory target. Could this B the 1?

Abstract

Section snippets

Induction of B1 receptors: how, where and when

Relevance of B1 receptors to inflammation

Concluding remarks

Acknowledgements

Glossary

Chemical names

J. Biol. Chem.

Eur. J. Pharmacol.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Immunopharmacology

Can. J. Physiol. Pharmacol.

Peptides

J. Immunol. Methods

Trends Neurosci.

Am. J. Physiol.

Ann. New York Acad. Sci.

Pharmacol. Rev.

Mol. Pharmacol.

Proc. Natl. Acad. Sci. U. S. A.

J. Clin. Invest.

Viewpoint
B₁ receptors as a new inflammatory target. Could this B the 1?

Induction of B₁ receptors: how, where and when

Relevance of B₁ receptors to inflammation