Bradykinin receptor antagonists

ACE inhibitors inhibit the degradation of bradykinin and potentiate the effects of bradykinin by about 50-100-fold. The prevention of bradykinin degradation by ACE inhibitors is particularly protective for the heart. Increased bradykinin levels prevent postischemic reperfusion arrhythmia, delays manifestations of cardiac ischemia, prevents platelet aggregation, and probably also reduces the degree of arteriosclerosis and the development of cardiac hypertrophy. The role of bradykinin and bradykinin-induced NO release for the improvement of cardiac functions by converting enzyme inhibitors has been demonstrated convincingly with use of a specific bradykinin receptor antagonist and inhibitors of NO-synthase. 

Meini S, Cucchi P, BeUucci F, et al. Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists. Biochem Pharmacol 2004 67 601-9. 

Bujalska M, Tatarkiewicz J, Gumulka SW Effect of bradykinin receptor antagonists on vincristine- and streptozotocin-induced hyperalgesia in a rat model of chemotherapy-induced and diabetic neuropathy. Pharmacology 2008 81 158. [PMID 17989505]... 

In the late 1980s when we began the pursuit of bradykinin receptor antagonists, information of relevance to medicinal chemists was scarce. For example, not one nonpeptide antagonist of this receptor was known, nor were any series upon which to base a structure-activity relationship. Moreover, all publications described bradykinin as being highly flexible in an aqueous environment, such that no structural mimetics could be rationalized. Of course the receptors had not been cloned at that time so nothing was known about the primary sequence of the receptor or the three-dimensional structure. 

Pyrimidine, (Y), triazines, and aniline-based bradykinin receptor antagonists, (Y), prepared by Olmeyer (4) were effective in treating inflammation, pain, and multiple sclerosis. 

Sakamoto, T., Elwood, W., Barnes, P.J. and Chung, K.F. (1992). Effect of Hoe 140, a new bradykinin receptor antagonist, on bradykinin- and platelet-activating factor-induced bronchoconstriction and airway microvascular leakage in guinea-pig. Eur. J. Pharmacol. 213, 367-373. 

BRADYKININ RECEPTOR ANTAGONIST affinity for the Bj-receptor subtype. It has been used as a pharmacological tool. lle-Ser-bradykinin T-kinin. 

Lys-[Leu ,desArg bradykinin (Lys-[Leu ,desArg ]BK) is a bradykinin receptor antagonist selective for the B -receptor subtype. 

R-493 (DArg-IHyp .oPheMeu lBK) is a substitued bradykinin analogue, a BRADYKININ receptor antagonist selective for the Bj-receptor subtype. 

Two pyrroloquinoline alkaloids, martinelline (49) and martinellic acid (50), have been isolated from an organic extract of root of Martinella iquitosensis A. Sampaio (Bigno-niaceae) by Witherup et al. (part of Merck s research group) as bradykinin receptor antagonists (Figure 10.11) [85]. The optical rotations of natural 49 and 50 were reported as [a]o +9.4 and -8.5, respectively, however the synthetic ( ) 50 showed a considerably larger value with the same sense ([a]o-122.7 [86,87] -164.3 [88]). A compound with the... 

D. J. Kyle, J. A. Martin, S. G. Farmer, and R. M. Burch, ]. Med. Chem., 34, 1230 (1991). Design and Conformational Analysis of Several Highly Potent Bradykinin Receptor Antagonists. 

Chakravarty, S., Mavunkel, B.J., Goehring, R.R. and Kyle, D.J., Novel bradykinin receptor antagonists from a structurally directed non-peptide combinatorial library, Im-munopharm., 33 (1996) 61-67. 

Martinelline 136 and martinellic acid 137 are classified as pyrroloquinoline alkaloids. They were isolated from the roots of the tropical plant, Martinella iquitosensis, and show bradykinin receptor antagonistic activity. Hamada and co-workers reported on a synthesis of the chiral marti-nellin core structures 134 and 135 via organocatalytic cascade reaction. Anthranilaldehyde 130 and enal 131 underwent Michael-aldol reaction in the presence of (S)-... 

Bas M. Bier H. Greve J, Kojda G, Hoffmann T Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant. Allergy 2006 61 1490-1492. 

Bork K. Frank J, Grundt B, Schlattmann P. Nussberger J. Kreuz W Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (icatibant). J Allergy Clin Immunol 2007 119 1497-1503. 

Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists. The bradykinin antagonist, which is used as an anticancer agent, is an example. The adamantane-based peptidic bradykinin analog was utilized in strucmre-activity relationship (SAR) studies on the bradykinin receptors and showed a potent activity in inhibition of bradykinin-induced cytokine release and stimulation of histamine release [142]. 

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