Probing the Bradykinin Receptor: Mapping the Geometric Topography Using Ethers of Hydroxyproline in Novel Peptides

Dj, Kyle; Ja, Martin; Rm, Burch; Jp, Carter; Lu, Shan; Meeker, Sonya; Jc, Prosser; Jp, Sullivan; Togo, J; Noronha-Blob, Lalita

doi:10.1007/978-3-0348-7321-5_63

Cited by 12 publications

(16 citation statements)

References 18 publications

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“…The second conformation consists of a trans amide for Set-Pro and a q(-turn centered on the proline residue. Neither of these conformations is compatible with the proposed [3-turn centered on ProT-Phe s [9], which may account for the poor affinity of this peptide. The NMR spectra of analog 6 agree with previous studies of Hoe 140 in that the introduction of D-TicT-Oic 8 stabilizes the 13-turn at this position [9].…”

Section: Resultssupporting

confidence: 61%

“…The introduction of conformational constraints has been successfully employed in the linear analogs, for example DTicT-Tic 8, D-Tic7-Oic 8 and D-trans-Hyp-(O-propyl)7-Oic 8 [6][7][8]. There is evidence that these modifications promote the stabilization of a type Ir [3-turn from residues 6-9 [9]. It has been noted that a type II' [3-turn with a D-amino acid in the i+l position, as in bradykinin antagonists, has a similar topography to a type I [3-turn conformation in an all-L-amino acid peptide, such as bradykinin [10].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclic hexapeptide antagonists of the bradykinin B2 receptor: Receptor binding and solution backbone conformation

Krstenansky¹,

Ho²,

Tahilramani³

et al. 1995

Lett Pept Sci

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Cyclic hexapeptide analogs of bradykinin, based on a folded receptor-bound model of bradykinin, were found to be able to antagonize the action of bradykinin at its B2 bradykinin receptor. The best of these, cyclo(D-Lys(Arg)-Phe-Ser-D-Tic-Oic-Arg) [compound 17], has affinities at the human and rat B2 bradykinin receptors of 230 and 8.5 nM, respectively, This potency is significant, since the analogs lack the C-terminal carboxylate group, residues 2-4 and the important interaction of Phe 5. These constrained analogs may serve as tools for the determination of the receptor-bound conformation of antagonists at the bradykinin receptor and for the design of even smaller and more potent antagonist analogs.

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Section: Resultssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Cyclic hexapeptide antagonists of the bradykinin B2 receptor: Receptor binding and solution backbone conformation

Krstenansky¹,

Ho²,

Tahilramani³

et al. 1995

Lett Pept Sci

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“…Different research groups support the hypothesis that high-affinity peptide antagonists of the B 2 receptor must adopt C-terminal i-turn conformations [10][11][12][13][14][15][16]. Moreover, there is the assumption that an N-terminal positive charge and a hydrophobic Cterminal i-turn are the minimum requirements for binding [17].…”

Section: Introductionmentioning

confidence: 99%

New conformationally homogeneous β‐turn antagonists of the human B₂ kinin receptor

Monteagudo

Calvani

Catrambone

et al. 2001

Journal of Peptide Science

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We have designed and synthesized a conformationally homogeneous series of cyclic pentapeptides of the general structure c[Pro-aa(i)-D-Tic-Oic-aa(i + 3)] which adopt a type-II' beta-turn conformation believed important for high affinity antagonism of the bradykinin (BK) B2 receptor. We incorporated D-Tic and octahydroindole-2-carboxylic acid (Oic) residues (present in known active antagonists) in a cyclic pentapeptide that would place the D-aa in the i + 1 position of the beta-turn and a proline as a bridge between the C- and N-termini sides of the turn. In positions i and i + 3 alkyl, aromatic, polar or charged amino acids could be introduced without dramatically changing the overall structure. Ten analogues were studied using 1H nuclear magnetic resonance (NMR) and evaluated for their binding affinity for the human B2 receptor. The NMR data in dimethylsulfoxide (DMSO) confirmed the structural homogeneity within the class and, on the basis of this, one representative member of the series was chosen for a detailed structure determination using NMR data in sodium dodecylsulphate (SDS) micelles and molecular dynamics calculations. Despite the structural similarity, the binding affinity of the ten analogues was strongly influenced by the nature of the side-chains in positions i and i + 3, with the doubly charged analogue 49 (pKi = 6.2) proving best. This compound may serve as the starting point for the discovery of new non-peptide bradykinin B2 receptor antagonists.

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“…Thus, some highly active compounds have been obtained, i.e. by replacement of the amino acids at position 7 and 8 with hydroxyproline ethers (16), d ‐Tic (17), d ‐Igl (18) or d ‐f5f (19), mostly combined with Oic. Some other attempts use the conformationally restricted antagonist [ d ‐Arg 0 , Hyp 3 , Thi 5 , d ‐Tic 7 , Oic 8 ]‐BK (Icatibant) (17) as a lead structure or use derived turn mimics (20–23) to stabilize the assumed active conformation.…”

mentioning

confidence: 99%

Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues

Schumann

Seyfarth

Greiner

et al. 2002

The Journal of Peptide Research

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A series of conformationally constrained cyclic analogues of the peptide hormone bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) was synthesized to check different turned structures proposed for the bioactive conformation of BK agonists and antagonists. Cycles differing in the size and direction of the lactam bridge were performed at the C- and N-terminal sequences of the molecule. Glutamic acid and lysine were introduced into the native BK sequence at different positions for cyclization through their side chains. Backbone cyclic analogues were synthesized by incorporation of N-carboxy alkylated and N-amino alkylated amino acids into the peptide chain. Although the coupling of Fmoc-glycine to the N-alkylated phenylalanine derivatives was effected with DIC/HOAt in SPPS, the dipeptide building units with more bulky amino acids were pre-built in solution. For backbone cyclization at the C-terminus an alternative building unit with an acylated reduced peptide bond was preformed in solution. Both types of building units were handled in the SPPS in the same manner as amino acids. The agonistic and antagonistic activities of the cyclic BK analogues were determined in rat uterus (RUT) and guinea-pig ileum (GPI) assays. Additionally, the potentiation of the BK-induced effects was examined. Among the series of cyclic BK agonists only compound 3 with backbone cyclization between positions 2 and 5 shows a significant agonistic activity on RUT. To study the influence of intramolecular ring closure we used an antagonistic analogue with weak activity, [D-Phe7]-BK. Side chain as well as backbone cyclization in the N-terminus of [D-Phe7]-BK resulted in analogues with moderate antagonistic activity on RUT. Also, compound 18 in which a lactam bridge between positions 6 and 9 was achieved via an acylated reduced peptide bond has moderate antagonistic activity on RUT. These results support the hypothesis of turn structures in both parts of the molecule as a requirement for BK antagonism. Certain active and inactive agonists and antagonists are able to potentiate the bradykinin-induced contraction of guinea-pig ileum.

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Probing the Bradykinin Receptor: Mapping the Geometric Topography Using Ethers of Hydroxyproline in Novel Peptides

Cited by 12 publications

References 18 publications

Cyclic hexapeptide antagonists of the bradykinin B2 receptor: Receptor binding and solution backbone conformation

Cyclic hexapeptide antagonists of the bradykinin B2 receptor: Receptor binding and solution backbone conformation

New conformationally homogeneous β‐turn antagonists of the human B₂ kinin receptor

Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues

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Probing the Bradykinin Receptor: Mapping the Geometric Topography Using Ethers of Hydroxyproline in Novel Peptides

Cited by 12 publications

References 18 publications

Cyclic hexapeptide antagonists of the bradykinin B2 receptor: Receptor binding and solution backbone conformation

Cyclic hexapeptide antagonists of the bradykinin B2 receptor: Receptor binding and solution backbone conformation

New conformationally homogeneous β‐turn antagonists of the human B2 kinin receptor

Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues

Contact Info

Product

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New conformationally homogeneous β‐turn antagonists of the human B₂ kinin receptor