Chimeric amino acids in cyclic bradykinin analogs: Evidence for receptor-bound turn conformation

Kaczmarek, Krzysztof; Li, K.-M.; Skeean, Richard W.; Dooley, David; Humblet, Christine; Lunney, Elizabeth A.; Marshall, Garland R.

doi:10.1007/978-94-011-0683-2_227

Cited by 11 publications

(15 citation statements)

References 6 publications

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“…Different conformational shapes for BK agonists have been proposed as a result of these investigations, e.g. random conformations (37,38), quasicyclic structures (34,39), turned structures at the N‐terminus (40), in the middle of the molecule (41,42) or at the C‐terminus (43–45). Studies with BK antagonists have suggested turned structures, in the N‐terminal sequence (between positions 2 and 5) (46,47), the C‐terminal sequence (between positions 6 and 9) (33,48,49) or in both fragments (32,35,36).…”

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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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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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“…13 C-NMR (CDCl 3 ) δ 169. 7,145.9,134.5,131.8,129.0,128.3,126.1,125.3,124.4,73.0,62.1,51.5,48.8,40.7,30.7,29.4. Anal.…”

Section: Methyl 1-benzamido-t-4-o-mesyl-t-2-(thien-2-yl)cyclohexane-rmentioning

confidence: 99%

“…2,3 Several β-substituted prolines ( Figure 1) have been synthesized as amino acid chimeras in which the functional groups of the amino acid side-chain are combined with the conformational restrictions characteristic of the cyclic amino acid residue. 4 Replacement of the natural amino acids in peptides with such proline-α-amino acid chimeras has led to better understanding of the bioactive conformations of cholecystokinin, 5 angiotensin II, 6 bradykinin, 7 and opioid peptides. 8,9 Also, β-alkylproline analogues have served for the development of enzyme inhibitors, 9,10 as well as peptidomimetics exhibiting improved bioactivity and greater metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 Also, β-alkylproline analogues have served for the development of enzyme inhibitors, 9,10 as well as peptidomimetics exhibiting improved bioactivity and greater metabolic stability. [6][7][8][9] The proline analogues which contain a 7-azabicyclo[2.2.1]heptane structure, Rb 7 Pro, constitute a distinct class of amino acids, owing to their extra conformational restriction ( Figure 1). Hence, the benefits of the parent compound (R = H), as a replacement for proline in a boroarginine thrombin inhibitor, 11 and as starting material in the synthesis of a new class of HIV-1 protease inhibitor, 12 have already been proved.…”

Section: Introductionmentioning

confidence: 99%

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Application of a new methodology for the synthesis and resolution of a ß-(thien-2-yl) proline with the 7-azanorbornane skeleton

Gil¹,

Buñuel²,

Cativiela³

2005

Arkivoc

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The enantiomers of a heavily constrained proline derivative, methyl (1S,2R,4R)-and (1R,2S,4S)-2-(thien-2-yl)-7-azabicyclo [2.2.1]heptane-1-carboxylate, have been obtained separately by resolution of the racemic mixture using chiral high performance liquid chromatography. This is a particular example of the application of our new methodology, which takes advantage of the efficiency of chromatographic resolution techniques for the preparation of both enantiomers of a broad variety of proline-α-amino acid chimeras with a 7-azanorbornane skeleton.

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“…1 Replacement of the natural amino acids in peptides for such proline-a-amino acid chimeras has led to a better understanding of the bioactive conformations. [2][3][4][5][6][7][8][9][10] Additionally, b-alkylproline analogues have served for the development of enzyme inhibitors, 11,12 as well as peptidomimetics exhibiting improved bioactivity and greater metabolic stability. 5,12 We are currently involved in a research project devoted to determining the conformational preferences of constrained analogues of proteinogenic amino acids when incorporated into a peptide chain.…”

Section: Introductionmentioning

confidence: 99%

New enantiopure 7-azanorbornane β-substituted prolines by SN2 displacements at the Cγ of the side chain

Gil

Orús

López‐Carrillo

et al. 2005

Tetrahedron: Asymmetry

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Chimeric amino acids in cyclic bradykinin analogs: Evidence for receptor-bound turn conformation

Cited by 11 publications

References 6 publications

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

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

Application of a new methodology for the synthesis and resolution of a ß-(thien-2-yl) proline with the 7-azanorbornane skeleton

New enantiopure 7-azanorbornane β-substituted prolines by SN2 displacements at the Cγ of the side chain

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