Syntheses and properties of new agonists and antagonists of bradykinin

Reißmann, Siegmund; Greiner, Georg; Schwuchow, C.; Castro, Luis Felipe Pineda De; Seyfarth, Lydia; Paegelow, I.; Liebmann, Claus; Wiesmüller, Karl‐Heinz

doi:10.1007/978-94-011-1470-7_317

Cited by 6 publications

(4 citation statements)

References 3 publications

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“…The BK analogue with NMePhe at position 2 (compound 26) has a moderate agonistic activity on RUT and acts in contrast as a weak antagonist on the guinea pig lung strip (Reissmann et al, 1993;Reissmann et al, submitted). Furthermore, at a concentration of 10~1 3 M it completely inhibited the BK induced cytokine release from mouse spleen cells (Paegelow et al, submitted).…”

Section: Discussionmentioning

confidence: 99%

New Photoaffinity Labelled Agonists of Bradykinin

Steinmetzer

Schumann²,

Paegelow³

et al. 1995

Biological Chemistry Hoppe-Seyler

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Several photoaffinity labelled agonists of the peptide hormone bradykinin (BK) were synthesized by solid phase methods. Their biological activities and binding affinities were determined in both the isolated rat uterus (RUT) and guinea pig ileum (GPI). As photoreactive groups p-benzoyl-phenylalanine (Bpa) and the arylazides azidobenzoic acid (ABA) and azidosalicylic acid (ASA) were attached to the N-terminus of the BK agonists. In addition, Bpa was incorporated at different positions of the BK sequence. Three different types of BK agonists were used. Firstly, the photolabels ASA and ABA were attached to BK or to Lys-BK (kallidin). Secondly, tyrosine containing BK analogues, suitable for radioiodination, were labelled. This series is derived from the naturally occurring analogue phyllokinin [BK-Ile-Tyr(SO3H)] and from BK analogues with tyrosine at position 0 and 3. The third series includes several analogues with D-N-methyl-phenylalanine (D-NMe-Phe) at position 7, which selectively discriminate between the RUT and GPI bradykinin B2 receptors. Among the photoaffinity labelled BK agonists, the iodinatable Lys(ASA)-BK (50.8% on RUT, 73.0% on GPI), ASA-BK (26.3% on RUT), Bpa-BK-Ile-Tyr (13.6% on RUT, 14.0% on GPI) and the iodinated [D-Bpa-1, 3-I-Tyr0]-BK (15.5% on RUT, 19.0% on GPI) retained a relatively high biological activity compared with BK (100%). Thus, although BK agonists are known to allow only very restricted modifications without a strong reduction in biological activity, these compounds should be useful candidates for receptor labelling.

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Section: Discussionmentioning

confidence: 99%

New Photoaffinity Labelled Agonists of Bradykinin

Steinmetzer

Schumann²,

Paegelow³

et al. 1995

Biological Chemistry Hoppe-Seyler

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“…Some of the modifications enhance while other reduce the biological activity. Thus bradykinin analogues with D-2,5-dimethylphenylalanine (Phe(2,5-Me)) and D-2,5-dimethylcyclohexylalanine (Cha(2,5-Me)) at position 7 display higher antagonistic activities on GPI and LS than DPhe [40]. While substitutions at the aliphatic or aromatic ring result in potent antagonists, substitutions at the C α -or C β -position in some cases destroy the antagonistic activity [40].…”

Section: Bradykinin Receptor Antagonistsmentioning

confidence: 97%

“…Thus bradykinin analogues with D-2,5-dimethylphenylalanine (Phe(2,5-Me)) and D-2,5-dimethylcyclohexylalanine (Cha(2,5-Me)) at position 7 display higher antagonistic activities on GPI and LS than DPhe [40]. While substitutions at the aliphatic or aromatic ring result in potent antagonists, substitutions at the C α -or C β -position in some cases destroy the antagonistic activity [40]. The very potent antagonist Icatibant (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTicOic-Arg, HOE-140) [41] was obtained by replacement of proline at position 7 by D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (DTic) and Phe at position 8 by 3αS, 7αS-octahydroindole-2-yl carboxylic acid (Oic) ( Table 1).…”

Section: Bradykinin Receptor Antagonistsmentioning

confidence: 98%

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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“…Thus, we replaced proline in position 7 by series of C a -and C b -substituted amino acids or ring-substituted phenylalanines ( [12], and manuscript in preparation). The substitution of proline in position 2 by N-methylphenylalanine provides an antagonist on the guinea pig lung strip without any other amino acid replacements in the sequence [13±15].…”

Section: Introductionmentioning

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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Syntheses and properties of new agonists and antagonists of bradykinin

Cited by 6 publications

References 3 publications

New Photoaffinity Labelled Agonists of Bradykinin

New Photoaffinity Labelled Agonists of Bradykinin

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

Bradykinin antagonists with dehydrophenylalanine analogues at position 5

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