Bradykinin agonists/antagonist

Methyl-quinolin-8-yloxymethyl derivatives, (IV), prepared by Carson (3) were effective as bradykinin agonists/antagonists and used in the management of pain and inflammation. 

Tissue-specific Agonists/Antagonists Tissue-type Plasminogen Activator T-kinin (Ile-Ser-Bradykinin)... 

Sawada Y, Kayakiri H, Abe Y, et al. A new class of nonpeptide bradykinin B2 receptor ligands, incorporating a 4-aminoquinoline framework. Identification of a key pharmacophore to determine species difference and agonist/antagonist profile. 7 Med Chem 2004 47 2667-77. 

Like angiotensin 11, non-peptide B2 receptor antagonists and agonists of bradykinin were obtained by random screening approaches. Chemical modifications on random screening leads like 101 led to non-peptide antagonists... 

There have been a variety of single alanine point mutations experimentally introduced into both rat and human bradykinin B2 receptors. Several of these have been shown to decrease the affinity of bradykinin to the receptor and have been implicated structurally near the agonist binding site. In contrast, at the time of this manuscript, there have been no mutations reported that adversely affect the ability of any peptide antagonists to bind to the receptor. Furthermore, antibodies raised against the certain extracellular domains of the kinin receptor compete with bradykinin for binding to the receptor but have no inhibitory... 

Table I lists agonists which have been found to be active in the renal vascular bed of the anesthetized dog. A few inactive compounds are included for comparison. Each agonist was antagonized selectively by a DA antagonist in a dose which does not affect vasodilation produced by bradykinin or isoproterenol. Compounds shown in Table I were studied in our laboratory under comparable conditions (2,4,5,7-10).

Kotovych, G., Cann, J. R,. Stewart, J. M., and Yamamoto, H. (1998) NMR and CD conformational studies of bradykinin and its agonists and antagonists application to receptor binding, Biochemistry and Cell Biology 76, 257-266. 

One final development worthy of note here is the development of novel anticancer agents that are dimeric bradykinin analogs. There has been a long-term interest in cross-linked kinin analogs as both agonists and antagonists of GPCRs... 

Chan, D., Gera, L., Stewart, J., et al. (2002) Bradykinin antagonist dimer, CU210, inhibits the growth of human lung eaneer eell lines by a biased agonist mechanism. Proc. Natl. Acad. Sci. USA 99, 4608 613. 

There seem few likely applications in therapeutics for bradykinin receptor agonists, though there are many putative applications for antagonists. However, the synthetic bradykinin B2 receptor agonist analogue RMP-7 is of some value for increasing cerebrovascular permeability in order to allow delivery to the brain of drugs that would otherwise not pass the blood-brain barrier (e.g. methotrexate and carboplatin in tumour treatment). 

Note of worth is also the successful replacement of the methyl ester with oxime ethers and Af-methoxy imidoyl nitrile in the design of muscarinic agonists (Figure 15.28). Several 1,2,4-oxadiazoles and the other five-mem-bered heterocycles are employed also for other therapeutic indications like monoamine transporter and opioid receptors,5-HT agonists, bradykinin Bi receptor antagonists, and vascular endothelial growth factor receptor (VEGFR-2) inhibitors. ... 

Leeb-Lundberg, L.M.F., Mathis, S.A., Herzig, M.C.S., 1994. Antagonists of bradykinin that stabilize a G-protein-uncoupled state of the B2 receptor act as inverse agonists in rat myometrial cells. J. Biol. Chem. 269, 25970-25973. 

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