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

100%

Manturewicz M. , Grzonka Z. , Borovickova L. , Slaninova J.

tom 54

nr 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 Gln 4 and Asn 5 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 Gln 4 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 Asn 5 by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn 5 and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group

Lysine-Vasopressin Analogues with Glycoconjugates in Position 8

100%

Marcinkowska A. , Borovickova L. , Slaninova J. , Grzonka Z.

2006

tom Vol. 80, nr 5

759-766

Two analogues of lysine-vasopressin in which the lysine side chain was modified by the attachment of glucuronic acid through the amide bond were synthesized and their pharmacological properties evaluated. In comparison to arginine-vasopressin used as a standard, both analogues were found to exhibit low activity in vasopressor test, moderate activity in antidiuretic test, and comparable activity in uterotonic test.

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

63%

Labudda O. , Wierzba T. , Sobolewski D. , Sleszynska M. , Gawinski L. , Plackova M. , Slaninova J. , Prahl A.

tom 54

nr 1

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.