Results found: 3

Number of results on page

Search results

Sort By:

Limit search:

Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9

100%

Manturewicz M., Grzonka Z., Borovičková L., Slaninová J.

Acta Biochimica Polonica

2007

vol. 54

issue 4

805-811

Eleven oxytocin analogues substituted in position 4, 5 or 9 by tetrazole analogues of amino acids were prepared using solid-phase peptide synthesis method and tested for rat uterotonic in vitro and pressor activities, as well as for their affinity to human oxytocin receptor. The tetrazolic group has been used as a bioisosteric substitution of carboxylic, ester or amide groups in structure-activity relationship studies of biologically active compounds. Replacement of the amide groups of Gln4 and Asn5 in oxytocin by tetrazole analogues of aspartic, glutamic and α-aminoadipic acids containing the tetrazole moiety in the side chains leads to analogues with decreased biological activities. Oxytocin analogues in which the glycine amide residue in position 9 was substituted by tetrazole analogues of glycine had diminished activities as well. The analysis of differences in rat uterotonic activity and in the affinity to human oxytocin receptors of analogues containing either an acidic 5-substituted tetrazolic group or a neutral 1,5- or 2,5-tetrazole nucleus makes it possible to draw some new conclusions concerning the role of the amide group of amino acids in positions 4, 5 and 9 of oxytocin for its activity. The data suggest that the interaction of the side chain of Gln4 with the oxytocin receptor is influenced mainly by electronic effects and the hydrogen bonding capacity of the amide group. Steric effects of the side chain are minor. Substitution of Asn5 by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn5 and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group.

New bradykinin B2 receptor antagonists - influence of C-terminal segment modifications on their pharmacological properties

64%

Śleszyńska M., Kwiatkowska A., Sobolewski D., Wierzba T., Katarzyńska J., Zabrocki J., Borovickova L., Slaninová J., Prahl A.

Acta Biochimica Polonica

2009

vol. 56

issue 4

641-648

In the present study we describe the synthesis and some pharmacological properties of eight new analogues of bradykinin (BK). Two peptides were designed by substitution of position 7 or 8 of the known [d-Arg0,Hyp3,Thi5,8,d-Phe7]BK antagonist (Stewart's antagonist) with l-pipecolic acid (l-Pip). The next two analogues were obtained by replacement of the d-Phe residue in position 7 of the Stewart's peptide with l-β2-isoproline (l-β2-iPro) or l-β3-homoproline (l-β3-hPro). The four analogues mentioned above were also prepared in N-acylated form with 1-adamantaneacetic acid (Aaa). Biological activity of the compounds was assessed by isolated rat uterus and rat blood pressure tests. Our results showed that l-Pip in position 7 slightly increased antagonistic potency in the blood pressure test, but it turned the analogue into an agonist in the rat uterus test. Replacement of Thi by l-Pip in position 8 also enhanced antagonism in the rat pressure test but preserved the antagonism in the rat uterus test. l-β2-iPro or l-β3-hPro in position 7 decreased the potencies in both tests. We also demonstrated that acylation of the N-terminus did not increase, as was claimed previously, the antagonistic potencies of the resulting peptides. The results thus support the hypothesis about the existence of different types of BK receptors in the rat uterus and blood vessels. Our studies provide new information about the structure-activity relationship of BK antagonists which may help in designing more potent BK receptor blockers.

New bradykinin analogues acylated on the N-terminus: effect on rat uterus and blood pressure

64%

Labudda O., Wierzba T., Sobolewski D., Śleszyńska M., Gawiński Ł., Plackova M., Slaninová J., Prahl A.

Acta Biochimica Polonica

2007

vol. 54

issue 1

193-198

Our previous studies suggested that acylation of the N-terminus of several known B2 antagonists with various kinds of bulky acyl groups consistently improved their antagonistic potency in rat blood pressure assay. On the other hand, our earlier observations also seemed to suggest that the effects of acylation on the contractility of isolated rat uterus depended substantially on the chemical character of the acyl group, as we observed that this modification might either change the range of antagonism or even transform it into agonism. Bearing all this in mind, we decided to synthesize seven new analogues of bradykinin by N-terminal acylation with various acyl groups of a moderately potent B2 antagonist, previously synthesized by Stewart's group, D-Arg-Arg-Pro-Hyp-Gly-Thr-Ser-D-Phe-Thi-Arg. The analogues were tested in vitro for their blood pressure-lowering and uterotonic activities. The modifications either preserved or increased the antagonistic potency in the rat blood pressure test. On the other hand, all seven substituents negatively influenced the interaction with the rat uterine receptors. Our results may be helpful for designing new B2 agonists and antagonists.

Refine search results

3 Acta Biochimica Polonica

1 2009

2 2007

3 Slaninová J.

2 Prahl A.

2 Sobolewski D.

2 Wierzba T.

2 Śleszyńska M.

1 Borovickova L.

1 Borovičková L.

1 Gawiński Ł.

1 Grzonka Z.

1 Katarzyńska J.

1 Kwiatkowska A.

1 Labudda O.

1 Manturewicz M.

1 Plackova M.

1 Zabrocki J.

Search results

Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9

New bradykinin B2 receptor antagonists - influence of C-terminal segment modifications on their pharmacological properties

New bradykinin analogues acylated on the N-terminus: effect on rat uterus and blood pressure