A new type of bradykinin B2 receptor antagonists: bradykinin analogs with N-alkyl amino acids at position 2

Reißmann, Siegmund; Greiner, Georg; Seyfarth, Lydia; Paegelow, I.; Werner, H.; Vietinghoff, Gabriele; Boeckmann, Sabine; Schulz, E.; Wartner, U; Gera, Lajos

doi:10.1016/0162-3109(96)00059-8

Cited by 8 publications

(11 citation statements)

References 16 publications

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“…Furthermore ring-substituted dehydrophenylalanine analogues were used to estimate the influence of the ring-substitution on the activity. From preceding work with bradykinin agonists and antagonists the necessity of estimating the bioactivity at different organs [9,13,14,15,24] had been established. Thus, the smooth muscle organs rat uterus (RUT), guinea pig ileum (GPI) and guinea pig pulmonary artery (PA) were used.…”

Section: Resultsmentioning

confidence: 99%

Bradykinin antagonists with dehydrophenylalanine analogues at position 5

et al. 1998

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Continuing the studies on structural requirements of bradykinin antagonists, it has been found that analogues with dehydrophenylalanine (deltaPhe) or its ring-substituted analogues (deltaPhe(X)) at position 5 act as antagonists on guinea pig pulmonary artery, and on guinea pig ileum. Because both organs are considered to be bradykinin B2 receptor tissues, the analogues with deltaPhe or deltaPhe(X) at position 5, but without any replacement at position 7, seem to represent a new structural type of B2 receptor antagonist. All the analogues investigated act as partial antagonists; they inhibit the bradykinin-induced contraction at low concentrations and act as agonists at higher concentrations. Ring substitutions by methyl groups or iodine reduce both the agonistic and antagonistic activity. Only substitution by fluorine gives a high potency. Incorporation of deltaPhe into different representative antagonists with key modifications at position 7 does not enhance the antagonist activity of the basic structures, with one exception. Only the combination of deltaPhe at position 5 with DPhe at position 7 increases the antagonistic potency on guinea pig ileum by about one order of magnitude. Radioligand binding studies indicate the importance of position 5 for the discrimination of B2 receptor subtypes. The binding affinity to the low-affinity binding site (KL) was not significantly changed by replacement of Phe by deltaPhe. In contrast, ring-methylation of deltaPhe results in clearly reduced binding to KL. The affinity to the high-affinity binding site (KH) was almost unchanged by the replacement of Phe in position 5 by deltaPhe, whereas the analogue with 2-methyl-dehydrophenylalanine completely failed to detect the KH-site. The peptides were synthesized on the Wang-resin according to the Fmoc/Bu(t) strategy using Mtr protection for the side chain of Arg. The dehydrophenylalanine analogues were prepared by a strategy involving PyBop couplings of the dipeptide unit Fmoc-Gly-deltaPhe(X)-OH to resin-bound fragments.

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Section: Resultsmentioning

confidence: 99%

Bradykinin antagonists with dehydrophenylalanine analogues at position 5

et al. 1998

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“…Thus, [LNMePhe 2 ]-BK represents a bradykinin antagonist without any amino acid replacement at position 7 (type 2 antagonists). This new lead structure inhibits the bradykinin-induced contraction of the guinea pig lung strip, the bronchoconstriction, the release of Ca + + from macrophages and exerts analgesic activity like antagonists carrying key replacement at position 7 [53]. Bradykinin analogues with LNMePhe at position 2 are also able to act as B 1 -receptor antagonists although they contain a Cterminal Arg [55].…”

Section: Bradykinin Receptor Antagonistsmentioning

confidence: 97%

“…Bradykinin analogues with LNMePhe at position 2 are also able to act as B 1 -receptor antagonists although they contain a Cterminal Arg [55]. Beside D/L-NMePhe only D/L-erythro-β-phenylserine (Ser(βPh)) and Tic at position 2 convert agonists into antagonists [53] (Table 1). All other replacements at position 2 by nonproteinogenic aromatic, alicyclic, aliphatic and N-alkyl amino acids led to agonistic or inactive analogues.…”

Section: Bradykinin Receptor Antagonistsmentioning

confidence: 98%

“…To study the influence of N-alkylation on biological activity, certain amino acid residues in bradykinin antagonists have been replaced by D-and L-N-methyl phenylalanine (D/LNMePhe) [52,53], N-cyclohexyl glycine (Nchg) [54], N-cycloheptyl glycine (Nc7g) [55], and N-(2-indanyl)glycine (Nig) [55], respectively. Combinations with above-mentioned D-amino acids at position 7 resulted in highly potent and stable antagonists [43,44,55].…”

Section: Bradykinin Receptor Antagonistsmentioning

confidence: 99%

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Development of Conformationally Restricted Analogues of Bradykinin and Somatostatin Using Constrained Amino Acids and Different Types of Cyclization

Reißmann

Imhof²

2004

CMC

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The structure-based design of peptide drugs requires the knowledge of the bioactive conformation. Studies on this receptor-bound 3D structure require linear or cyclic analogues with strongly reduced flexibility, but high biological activity, since only analogues with retained potency have preserved the bioactive conformation. Constrained amino acids containing double bonds or bulky substituents at the N(alpha)-, C(alpha)- and C(beta)-atom as well as at the aromatic ring atom were successfully applied to obtain potent and stable analogues of bradykinin and somatostatin, which due to their restricted conformation were suitable objects for conformational studies. Besides the generation of constrained cyclic analogues with improved biological and pharmacological properties, cyclic peptides were used as convenient models for the study of turn formations. Cyclization of the linear peptide bradykinin was performed by linking the N-terminus and the C-terminus, and in both bradykinin and somatostatin by cyclization using the amino acid side chains and by backbone cyclization. The later requires the introduction of N(alpha)-functionalised amino acids for ring closure which can be performed either through incorporation of N(alpha)-functionalised amino acids or dipeptide building units. Conformational analysis of a cyclic bradykinin analogue by means of NMR-studies together with molecular dynamics simulation led to a quasicyclic 3D structure with two turns and together with other 3D structures provided a pharmacophore model of bradykinin antagonists.

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“…Therefore bradykinin antagonists are of great therapeutical interest. We assume that there exist three structural types of bradykinin B 2 receptor antagonists derived by amino acid replacements at position 2 (type-2-antagonists) [11,12] at position 5 (type-5-antagonists) [13] and mainly at position 7 (type-7-antagonists) [10,14]. We were interested to replace proline at position 2 and 7 by conformationally restricted amino acids like ortho-as well as meta amino benzoic acid (o-Aba, m-Aba) and cis-4-hydroxyproline (cis-Hyp).…”

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confidence: 99%

Combination of allyl protection and HYCRAMTM-linker technology for the synthesis of peptides with problematical amino acids and sequences

Gothe¹,

Seyfarth²,

Schumann³

et al. 1999

J. prakt. Chem.

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Abstract. Analogues of both the nonapeptides, bradykinin and bradykinin potentiating nonapeptide BPP 9α , were synthesized using HYCRAM™-technique. The bradykinin analogues were assembled by the Boc-, Ddz-and Fmoc-strategy starting with Boc-Arg(Aloc) 2 -OCr-OH, Ddz-Arg(Mtr)-OCr-OH and Fmoc-Arg(Mtr)-OCr-OH. While Boc-and Ddz-strategy provide peptides in good yield and purity, the Fmoc-strategy leads to a loss of peptide from resin. For simultaneous cleavage from HYCRAM™-resin and removal of Aloc-side chain protection optimized conditions for catalytic cleavage with Pd° were developed. As shown by the synthesis of BPP 9α analogues the HYCRAM™-linker and the chlorotrityl resin Solid phase syntheses of peptides with sensitive amino acids or sensitive pseudopeptide bonds require special linkers, which are stable under the conditions of coupling and deprotection and very smoothly to cleave without strong acidic or basic conditions. With the development of the hydroxycrotonoyl amino methyl linker (HYCRAM TM ) by Kunz et al. [1,2,3] and Birr [4, 5] a linker was found which fulfills these requirements in a good manner. The assembled peptides can be removed from the resin by treatment with Pd[P(C 6 H 5 ) 3 ] 4 as catalyst under nearly neutral conditions. Catalysts, scavallow the assembly of peptides with the C-terminal sequence Pro-Pro by preventing dioxopiperazine formation. Since the BPP 9α sequence contains the tripeptide Trp-X-Arg an intramolecular migration of the N G -protecting group to the indole ring under conditions used for its removal had to be avoided. By the use of HYCRAM™-linker in combination with Aloc protection for the guanidino group and Ddz for N α no modification of Trp occurred. HYCRAM™-technology in combination with Boc-, Ddz-or Aloc/All-protecting groups facilitates the synthesis of peptides with such very labile amino acids like cis-4-hydroxyproline. 1 ) Other abbreviations include: o-Aba; m-Aba, ortho, meta amino benzoic acid; Aloc, allyl oxycarbonyl; BK, bradykinin; Boc, tert-butyloxycarbonyl; BPP 9α , bradykinin potentiating peptide 9α (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro); BOP, benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate; Bu 3 SnH, tributyltin hydride; Bu

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A new type of bradykinin B2 receptor antagonists: bradykinin analogs with N-alkyl amino acids at position 2

Cited by 8 publications

References 16 publications

Bradykinin antagonists with dehydrophenylalanine analogues at position 5

Bradykinin antagonists with dehydrophenylalanine analogues at position 5

Development of Conformationally Restricted Analogues of Bradykinin and Somatostatin Using Constrained Amino Acids and Different Types of Cyclization

Combination of allyl protection and HYCRAMTM-linker technology for the synthesis of peptides with problematical amino acids and sequences

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