Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Bradykinin receptor ligands: therapeutic perspectives

Nature Reviews Drug Discovery volume 3, pages 845–852 (2004)Cite this article

Key Points

  • The kallikrein–kinin system consists of the precursor kininogens, the proteolytic kallikrein enzymes, the kinin peptides (which are produced through cleavage of kininogens by kallikreins) and two G-protein-coupled receptors (GPCRs), termed the B1 and B2 receptors, that mediate the biological effects of kinin peptides.

  • The growing knowledge of the biological role of kinins has fuelled the development of potent and selective kinin receptor modulators as potential therapeutics.

  • This medicinal chemistry effort, which was initiated with peptides in the 1970s, has now culminated in the production of a number of novel non-peptide antagonists, some of which are awaiting clinical trials.

  • This article provides an overview of the kinin biology that is relevant to the roles of kinins in disease, and then considers the potential of kinin receptor modulators in various disease indications, including inflammation and pain.

Abstract

Kinins, which are produced by the action of kallikrein enzymes, are blood-derived local-acting peptides that have broad effects mediated by two related G-protein-coupled receptors termed the bradykinin receptors. The endogenous kallikrein–kinin system controls blood circulation and kidney function, and promotes inflammation and pain in pathological conditions, which has led to interest in developing modulators of bradykinin receptors as potential therapeutics. This review discusses recent progress in our understanding of the genetics, molecular biology and pathophysiology of kinins and their receptors, as well as developments in medicinal chemistry, which have brought us closer to therapeutic applications of kinin receptor ligands in various indications. The potential of kinin receptor antagonists as novel analgesic agents that do not result in tolerance or have a liability for abuse has attracted particular interest.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of the kallikrein–kinin system.
Figure 2: Peptide receptor ligands of the mammalian kinin receptors.
Figure 3: Non-peptide antagonists for bradykinin receptors.

Similar content being viewed by others

References

  1. Blais, C. Jr, Marceau, F., Rouleau, J. L. & Adam, A. The kallikrein–kininogen–kinin system: lessons from the quantification of endogenous kinins. Peptides 21, 1903–1940 (2000).

    Article  CAS  Google Scholar 

  2. Linz, W., Wiemer, G., Gohlke, P., Unger, T. & Shoelkens, B. A. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol. Rev. 47, 25–49 (1995).

    CAS  PubMed  Google Scholar 

  3. Gainer, J. V., Morrow, J. D., Loveland, A., King, D. J. & Brown, N. J. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N. Engl. J. Med. 339, 1285–1292 (1998).

    Article  CAS  Google Scholar 

  4. Squire, I. B., O'Kane, K. P., Anderson, N. & Reid, J. L. Bradykinin B2 receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men. Hypertension 36, 132–136 (2000).

    Article  CAS  Google Scholar 

  5. Regoli, D. & Barabé, J. Pharmacology of bradykinin and related kinins. Pharmacol. Rev. 32, 1–46 (1980).

    CAS  PubMed  Google Scholar 

  6. Marceau, F., Hess, J. F. & Bachvarov, D. R. The B1 receptors for kinins. Pharmacol. Rev. 50, 357–386 (1998).

    CAS  PubMed  Google Scholar 

  7. McEachern, A. E. et al. Expression cloning of a rat B2 bradykinin receptor. Proc. Natl Acad. Sci. USA 88, 7724–7728 (1991).

    Article  CAS  Google Scholar 

  8. Menke, J. G. et al. Expression cloning of a human B1 bradykinin receptor. J. Biol. Chem. 269, 21583–21586 (1994).

    CAS  PubMed  Google Scholar 

  9. Borkowski, J. A. et al. Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J. Biol. Chem. 270, 13706–13710 (1995).

    Article  CAS  Google Scholar 

  10. Pesquero, J. B. et al. Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc. Natl Acad. Sci. USA 97, 8140–8145 (2000).

    Article  CAS  Google Scholar 

  11. Alfie, M. E., Sigmon, D. H., Pomposiello, S. I. & Carretero, O. A. Effect of high salt intake in mutant mice lacking bradykinin-B2 receptors. Hypertension 29, 483–487 (1997).

    Article  CAS  Google Scholar 

  12. Cayla, C. et al. Structure of the mammalian kinin receptor gene locus. Int. Immunopharmacol. 2, 1721–1727 (2002).

    Article  CAS  Google Scholar 

  13. Dhamrait, S. S. et al. Variation in bradykinin receptor genes increases the cardiovascular risk associated with hypertension. Eur. Heart. J. 24, 1672–1680 (2003). A number of polymorphisms of the human kinin receptor gene locus are now known. Although much remains to be done to define haplotypes related to human disease, this article reports the largest population tested for disease predisposition predicted by SNPs or a small insertion/deletion mutations.

    Article  CAS  Google Scholar 

  14. Dziadulewicz, E. K. et al. Nonpeptide bradykinin B2 receptor antagonists: conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists. J. Med. Chem. 45, 2160–2172 (2002).

    Article  CAS  Google Scholar 

  15. Su, D. et al. Discovery of a potent, non-peptide bradykinin B1 receptor antagonist. J. Am. Chem. Soc. 125, 7516–7517 (2003).

    Article  CAS  Google Scholar 

  16. Gougat, J. et al. SSR240612, a new non-peptide antagonist of the bradykinin B1 receptor. Biochemical and pharmacological characterization. J. Pharmacol. Exp. Ther. 309, 661–669 (2004).

    Article  CAS  Google Scholar 

  17. Ritchie, T. J. et al. Potent and orally bioavailable non-peptide antagonists at the human bradykinin B1 receptor based on a 2-alkylamino-5-sulfamoylbenzamide core. J. Med. Chem. 47, 4642–4644 (2004).

    Article  CAS  Google Scholar 

  18. Emerich, D. F. et al. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin. Pharmacokinet. 40, 105–123 (2001).

    Article  CAS  Google Scholar 

  19. Emanueli, C. et al. Targeting kinin B1 receptor for therapeutic neovascularization. Circulation 105, 360–366 (2002). This and previous articles support the idea that kinin receptors (mostly B 1 ) mediate inflammatory or ischaemic angiogenesis/neovascularization.

    Article  CAS  Google Scholar 

  20. Schmaier, A. H. The physiologic basis of assembly and activation of the plasma kallikrein/kinin system. Thromb. Haemost. 91, 1–3 (2004).

    Article  CAS  Google Scholar 

  21. Mahdi, F. et al. Mapping the interaction between high molecular weight kininogen and the urokinase plasminogen activator receptor. J. Biol. Chem. 279, 16621–16628 (2004).

    Article  CAS  Google Scholar 

  22. Margolius, H. S. Tissue kallikreins structure, regulation, and participation in mammalian physiology and disease. Clin. Rev. Allergy Immunol. 16, 337–349 (1998).

    Article  CAS  Google Scholar 

  23. Stadnicki, A. et al. Immunolocalization and expression of kallistatin and tissue kallikrein in human inflammatory bowel disease. Dig. Dis. Sci. 48, 615–623 (2003).

    Article  CAS  Google Scholar 

  24. Batenburg, W. W., Garrelds, I. M., van Kats, J. P., Saxena, P. R. & Danser, A. H. Mediators of bradykinin-induced vasorelaxation in human coronary microarteries. Hypertension 43, 488–492 (2004).

    Article  CAS  Google Scholar 

  25. Christiansen, S. C. et al. Up-regulation of functional kinin B1 receptors in allergic airway inflammation. J. Immunol. 169, 2054–2060 (2002). Reports B 1 receptor induction at work in clinically relevant material from allergic patients.

    Article  CAS  Google Scholar 

  26. Passos, G. F. et al. Kinin B1 receptor up-regulation after lipopolysaccharide administration: role of proinflammatory cytokines and neutrophil influx. J. Immunol. 172, 1839–1847 (2004).

    Article  CAS  Google Scholar 

  27. Souza, D. G. et al. Role of bradykinin B2 and B1 receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury. J. Immunol. 172, 2542–2548 (2004).

    Article  CAS  Google Scholar 

  28. Blaukat, A. et al. Overexpression and functional characterization of kinin receptors reveal subtype-specific phosphorylation. Biochemistry 38, 1300–1309 (1999).

    Article  CAS  Google Scholar 

  29. Bachvarov, D. R. et al. Bradykinin B2 receptor endocytosis, recycling, and down-regulation assessed using green fluorescent protein conjugates. J. Pharmacol. Exp. Ther. 297, 19–26 (2001).

    CAS  PubMed  Google Scholar 

  30. Sabourin, T., Bastien, L., Bachvarov, D. R. & Marceau, F. Agonist-induced translocation of the kinin B1 receptor to caveolae-related rafts. Mol. Pharmacol. 61, 546–553 (2002).

    Article  CAS  Google Scholar 

  31. Pretorius, M., Rosenbaum, D., Vaughan, D. E. & Brown, N. J. Angiotensin-converting enzyme inhibition increases human vascular-type plasminogen activator release through endogenous bradykinin. Circulation 107, 579–585 (2003).

    Article  Google Scholar 

  32. Molinaro, G. et al. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine9-bradykinin. J. Pharmacol. Exp. Ther. 303, 232–237 (2002).

    Article  CAS  Google Scholar 

  33. Sulpizio, A., Pullen, M. A., Edwards, R. M. & Brooks, D. P. The effect of acute angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition on plasma extravasation in the rat. J. Pharmacol. Exp. Ther. 309, 1141–1147 (2004).

    Article  CAS  Google Scholar 

  34. Hornig, B., Kohler, C., Schlink, D., Tatge, H. & Drexler, H. AT1-receptor antagonism improves endothelial function in coronary artery disease by a bradykinin/B2-receptor-dependent mechanism. Hypertension 41, 1092–1095 (2003).

    Article  CAS  Google Scholar 

  35. Katada, J. & Majima, M AT2 receptor-dependent vasodilation is mediated by activation of vascular kinin generation under flow conditions. Br. J. Pharmacol. 136, 484–491 (2002).

    Article  CAS  Google Scholar 

  36. Aliberti, J. et al. Cutting edge: bradykinin induces IL-12 production by dendritic cells: a danger signal that drives Th1 polarization. J. Immunol. 170, 5349–5553 (2003). The effect of kinins on leukocytes is a relatively neglected topic; this study supports an immunopharmacological effect mediated by B 2 receptors.

    Article  CAS  Google Scholar 

  37. Gobeil, F. et al. Kinin B1 receptor antagonists containing α-methyl-L-phenylalanine: in vitro and in vivo antagonistic activities. Hypertension 33, 823–829 (1999).

    Article  CAS  Google Scholar 

  38. Neugebauer, W. et al. B1 receptor antagonists with multienzymatic resistance properties. Can. J. Physiol. Pharmacol. 80, 287–292 (2002).

    Article  CAS  Google Scholar 

  39. Gera, L., Stewart, J. M., Whalley, E. T., Burkard, M. & Zuzack, J. S. New bradykinin antagonists having very high potency at B1 receptors. Immunopharmacology 33, 183–185 (1996).

    Article  CAS  Google Scholar 

  40. Vavrek, R. J. & Stewart, J. M. Competitive antagonists of bradykinin. Peptides 6, 161–164 (1985).

    Article  CAS  Google Scholar 

  41. Stewart, J. M. Bradykinin antagonists: discovery and development. Peptides 25, 527–532 (2004).

    Article  CAS  Google Scholar 

  42. Hock, F. J. et al. Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br. J. Pharmacol. 102, 769–773 (1991). Initial pharmacological characterization of an immensely successful research reagent, presently in clinical development for hereditary angioedema and refractory ascites in liver cirrhosis.

    Article  CAS  Google Scholar 

  43. Chan, D. et al. Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a «biased agonist» mechanism. Proc. Natl Acad. Sci. USA 99, 4608–4613.

  44. Asano, M. et al. The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657. Br. J. Pharmacol. 120, 617–624 (1997).

    Article  CAS  Google Scholar 

  45. Pruneau, D. et al. Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist. Immunopharmacology 43, 187–194 (1999).

    Article  CAS  Google Scholar 

  46. Griesbacher, T. & Legat, F. J. Effects of the non-peptide B2 receptor antagonist FR173657 in models of visceral and cutaneous inflammation. Inflamm. Res. 49, 535–540 (2000).

    Article  CAS  Google Scholar 

  47. Uknis, A. B. et al. Bradykinin receptor antagonists type 2 attenuate the inflammatory changes in peptidoglycan-induced acute arthritis in the Lewis rat. Inflamm. Res. 50, 149–155 (2001).

    Article  CAS  Google Scholar 

  48. Samadfam, R. et al. Contribution of B2 receptors for bradykinin in Arthus reaction-induced plasma extravasation in wild-type or B2 transgenic knockout mice. Br. J. Pharmacol. 129, 1732–1738 (2000).

    Article  CAS  Google Scholar 

  49. Kaplanski, J. et al. LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces brain edema and improves long-term neurological function recovery after closed head trauma in rats. J. Neurotrauma 19, 953–964 (2002).

    Article  Google Scholar 

  50. Zausinger, S. et al. Effects of LF 16-0687 Ms, a bradykinin B2 receptor antagonist, on brain edema formation and tissue damage in a rat model of temporary focal cerebral ischemia. Brain Res. 950, 268–278 (2002).

    Article  CAS  Google Scholar 

  51. Narotam, P. K. et al. Traumatic brain contusions: a clinical role for the kinin antagonist CP-0127. Acta Neurochir. (Wien) 140, 793–802 (1998).

    Article  CAS  Google Scholar 

  52. Eric, J., Gabra, B. H. & Sirois, P. Implication of the bradykinin receptors in antigen-induced pulmonary inflammation in mice. Br. J. Pharmacol. 138, 1589–1597 (2003).

    Article  CAS  Google Scholar 

  53. Burgess, G. M. et al. Bradyzide, a potent non-peptide B2 receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia. Br. J. Pharmacol. 129, 77–86 (2000).

    Article  CAS  Google Scholar 

  54. Levy, D. & Zochodne, D. W. Increased mRNA expression of the B1 and B2 bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain. Pain 86, 265–271 (2000).

    Article  CAS  Google Scholar 

  55. Ma, Q. P. & Heavens, R. Basal expression of bradykinin B1 receptors in the spinal cord in humans and rats. Neuroreport 12, 2311–2314 (2001).

    Article  CAS  Google Scholar 

  56. Wotherspoon, G. & Winter, J. Bradykinin B1 rerceptor is constitutively expressed in the rat sensory nervous system. Neurosci. Lett. 294, 175–178 (2000).

    Article  CAS  Google Scholar 

  57. Ongali, B. et al. Autoradiographic analysis of rat brain kinin B1 and B2 receptors: normal distribution and alterations induced by epilepsy. J. Comp. Neurol. 461, 506–519 (2003).

    Article  CAS  Google Scholar 

  58. Bregola, G. et al. Changes in hippocampal and cortical B1 bradykinin receptor biological activity in two experimental models of epilepsy. Neuroscience 92, 1043–1049 (1999).

    Article  CAS  Google Scholar 

  59. Hess, J. F. et al. Generation and characterization of a human bradykinin receptor B1 transgenic rat as a pharmacodynamic model. J. Pharmacol. Exp. Ther. 310, 488–497 (2004).

    Article  CAS  Google Scholar 

  60. Fein, A. M. et al. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group. JAMA 277, 482–487 (1997).

    Article  CAS  Google Scholar 

  61. Gabra, B. H. & Sirois, P. Role of bradykinin B1 receptors in diabetes-induced hyperalgesia in streptozotocin-treated mice. Eur. J. Pharmacol. 457, 115–124 (2002).

    Article  CAS  Google Scholar 

  62. Zuccollo, A. et al. The involvement of kallikrein-kinin system in diabetes type I (insulitis). Immunopharmacology 45, 69–74 (1999).

  63. Wang, C. H. et al. Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats: Studies comparing a vasopeptidase inhibitor, angiotensin-converting enzyme inhibitor, and angiotensin II type I receptor blocker. Circulation 107, 1923–1929 (2003). There is a hierarchy of antihypertensive agents theoretically capable of recruiting endogenous bradykinin to improve the sensitivity to insulin: the dual peptidase inhibitor omapatrilat is the most effective, followed by an ACE inhibitor. An angiotensin type-1 receptor antagonist is inactive.

    Article  CAS  Google Scholar 

  64. Shiuchi, T. et al. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension 40, 329–334 (2002).

    Article  CAS  Google Scholar 

  65. Izhar, M., Alausa, T., Folker, A., Hung, E. & Bakris, G. L. Effects of COX inhibition on blood pressure and kidney function in ACE inhibitor–treated blacks and hispanics. Hypertension 43, 573–577 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

F.M.'s laboratory is supported by the Canadian Institutes for Health Research.

Author information

Authors and Affiliations

  1. Centre de Recherche, Centre Hospitalier Universitaire de Québec, Pavillon L'Hôtel-Dieu de Québec, 11 Côte-du-Palais, Québec, G1R 2J6, Canada

    François Marceau

  2. Institute of Pharmacology, Faculty of Medicine, University of Ferrara, Via F. di Mortara 19, Ferrara, 44100, Italy

    Domenico Regoli

Authors
  1. François Marceau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Domenico Regoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

ACE

AT1 receptor

AT2 receptor

B1 receptor

B2 receptor

BK

Hageman factor

IL-12

neutral endopeptidase

NF-κB

tissue kallikrein

OMIM

Inflammatory bowel disease

Glossary

LINKAGE DISEQUILIBRIUM

The association between a pair of allelic variants that occurs more often than by chance.

CONTACT SYSTEM

A complex derived from four plasma proteins that is self-assembled when blood encounters a negatively charged surface.

ZYMOGEN

A proenzyme. Requires enzymatic activation to exert its own effects.

RENIN–ANGIOTENSIN SYSTEM

The renin–angiotensin system is a key regulator of blood pressure.

LIPOPOLYSACCHARIDE

A constituent of the cell walls of Gram-negative bacteria that is thought to be important for eliciting the immune response to Gram-negative bacterial infection. Also known as endotoxin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marceau, F., Regoli, D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 3, 845–852 (2004). https://doi.org/10.1038/nrd1522

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1522

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing