Characterization of non-peptide bradykinin B2 receptor agonist (FR 190997) and antagonist (FR 173657)

Gobeil, Fernand; Montagne, Martin; Inamura, Noriaki; Regoli, Doménico

doi:10.1016/s0162-3109(99)00129-0

Cited by 23 publications

(11 citation statements)

References 11 publications

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“…Therefore, we conclude that peptide B 1 receptor antagonists should be designed to achieve noncompetitive antagonism and long-lasting effect in vivo. Indeed, under the same experimental condition in anesthetized rabbits, HOE 140 harbors a duration of action in vivo that is significantly longer (Ͼ90 minutes) 37 …”

Section: Discussionmentioning

confidence: 98%

Kinin B ₁ Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

et al. 1999

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Abstract-To␣ Me)Phe analogues showed high antagonistic potencies (pA 2 ) at both the human (8.8, 7.7, and 8.7, respectively) and rabbit (8.6, 7.8, and 8.6, respectively) B 1 receptors. No antagonistic effects (pA 2 Ͻ5) were observed on the B 2 receptors that mediate the contractile effects of BK on the human umbilical vein, the rabbit jugular vein, and the guinea pig ileum. Moreover, these new B 1 antagonists were found to be resistant to in vitro degradation by purified angiotensin-converting enzyme from rabbit lung. The N ␣ -acetylated forms, R 892 and R 914, were resistant to aminopeptidases from human plasma. In vivo antagonistic potencies (ID 50 ) of B 1 receptor antagonists were evaluated in anesthetized lipopolysaccharide-treated (for B 1 receptor) and nontreated (for B 2 receptor) rabbits against the hypotensive effects of exogenous desArg 9 BK and BK. R 892 efficiently inhibited (ID 50 2.8 nmol/kg IV) hypotension induced by desArg 9 BK without affecting that evoked by BK (ID 50 Ͼ600 nmol/kg IV

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Section: Discussionmentioning

confidence: 98%

Kinin B ₁ Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

et al. 1999

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“…, 2000; Hayashi et al. , 2001) as well as a propensity for prolonged desensitization of the B 2 receptor in some systems (Cuthbert, 1999; Gobeil et al. , 1999).…”

Section: Introductionmentioning

confidence: 99%

Effects of inactivation‐resistant agonists on the signalling, desensitization and down‐regulation of bradykinin B₂ receptors

Bawolak

Fortin

Bouthillier

et al. 2009

British J Pharmacology

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Background and purpose: A peptide bradykinin (BK) B2 receptor agonist partially resistant to degradation, B-9972, downregulates this receptor subtype. We have used another recently described non-peptide agonist, compound 47a, as a tool to study further the effects of metabolically more stable and thus persistent, agonists of the BK B2 receptor on signalling, desensitization and down-regulation of this receptor.

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“…Extensive reports on the pharmacology of 19a have been published by others and us. [21][22][23][24][25][26][27][28][29][30][31] According to these reports, the binding mode of 19a to the B 2 receptor seems to depend on the species, tissues, and experimental conditions. 25 Table 3 summarizes the results of optimization studies on the acyl side chain of 19a.…”

Section: Resultsmentioning

confidence: 99%

Discovery of the First Non-Peptide Full Agonists for the Human Bradykinin B₂ Receptor Incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole Frameworks

Sawada¹,

Kayakiri²,

Abe³

et al. 2004

J. Med. Chem.

109

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In the course of our studies on non-peptide bradykinin (BK) B(2) receptor ligands, it was suggested that the 4-substituent of the quinoline ring may play a critical role in determining binding affinities for human and guinea pig B(2) receptors, as well as agonist/antagonist properties. We carried out an extensive investigation to elucidate the structure-activity relationships (SAR) for this key pharmacophore. Introduction of lower alkoxy groups to the 4-position of the quinoline ring of 3 led to the identification of 4-ethoxy derivative 22b as a unique partial agonist. This compound significantly stimulated inositol phosphates (IPs) formation in Chinese hamster ovary cells expressing the cloned human B(2) receptor at concentrations greater than 10 nM and displayed one-tenth of the intrinsic activity of BK. The agonist activity of 22b was selective for the B(2) receptor and was inhibited by selective peptide and non-peptide B(2) antagonists. On the other hand, 22b strongly suppressed BK-induced IPs formation through the cloned human B(2) receptor. Further studies on the key pharmacophore led to identification of a 2-picolyloxy moiety as a powerful agonist switch, leading to the discovery of a potent and efficacious non-peptide B(2) agonist, 19a. Successive optimization of the acyl side chain afforded 38, which exhibited full agonist activity on stimulation of IPs formation. Furthermore, this strategy could be applied successfully to the benzimidazole series. The representative 1-(2-picolyl)benzimidazole derivative 47c increased PGE(2) production at a 1 microM concentration to the same level as the maximum effect of BK. Thus, we have established the medicinal chemistry modifications required to convert our highly potent non-peptide B(2) antagonists to agonists with potent efficacy.

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Characterization of non-peptide bradykinin B2 receptor agonist (FR 190997) and antagonist (FR 173657)

Cited by 23 publications

References 11 publications

Kinin B ₁ Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Kinin B ₁ Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Effects of inactivation‐resistant agonists on the signalling, desensitization and down‐regulation of bradykinin B₂ receptors

Discovery of the First Non-Peptide Full Agonists for the Human Bradykinin B₂ Receptor Incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole Frameworks

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Characterization of non-peptide bradykinin B2 receptor agonist (FR 190997) and antagonist (FR 173657)

Cited by 23 publications

References 11 publications

Kinin B 1 Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Kinin B 1 Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Effects of inactivation‐resistant agonists on the signalling, desensitization and down‐regulation of bradykinin B2 receptors

Discovery of the First Non-Peptide Full Agonists for the Human Bradykinin B2 Receptor Incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole Frameworks

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Kinin B ₁ Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Kinin B ₁ Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Effects of inactivation‐resistant agonists on the signalling, desensitization and down‐regulation of bradykinin B₂ receptors

Discovery of the First Non-Peptide Full Agonists for the Human Bradykinin B₂ Receptor Incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole Frameworks