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1

Solution structure of conformationally restricted vasopressin analogues

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Trzepalka E. , Oleszczuk M. , Maciejczyk M. , Lammek B.

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nr 1

EN

In recent years, a massive effort has been directed towards designing potent and selective antagonists of neurohypophyseal hormones substituted at position 3. Modification of vasopressin at position 3 with 4,4'-biphenylalanine results in pharmacologically inactive analogues. Chemically, this substitution appears to vary only slightly from those previously made by us (1-Nal or 2-Nal), which afforded potent agonists of V2 receptors. In this situation, it seemed worthwhile to study the structure of the analogues with 4,4-biphenylalanine (BPhe) at position 3 in aqueous solution using NMR spectroscopy and total conformational analysis. This contribution is part of extensive studies aimed at understanding spatial structures of 3-substituted [Arg8 ]vasopressin analogues of different pharmacological properties. NMR data were used to calculate 3D structures for all the analogues using two methods, EDMC with the ECEPP/3 force field, and molecular dynamic with the simulated annealing (SA) algorithm. The structures obtained by the first method show a better fit between the NMR spectral evidence and the calculation for all the peptides.

2

The influence of modification at position 2 on the side-chain conformation in oxytocin analogs

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Smiech B. , Kazmierkiewicz R. , Lammek B.

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tom 53

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nr 1

EN

The nonapeptide oxytocin (OT) is used in medicine to help begin and/or continue childbirth. Its analogs can be also used to control bleeding following fetus delivery. The main function of oxytocin is to stimulate contraction of uterus smooth muscle and the smooth muscle of mammary glands, thus regulating lactation. This paper describes theoretical simulations of the distribution of the torsional angles χ1 in the non-standard methylated phenylalanine residues of three oxytocin analogs: [(Phe)2o-Me]OT, [(Phe)2m-Me]OT, [(Phe)2p-Me]OT. The conformations of the oxytocin analogs were studied both in vacuum and in solution. We found some correlations between the biological activity of the considered peptides and the side-chain conformations of amino-acid residues 2 and 8.

3

New Analogues of Bradykinin Substituted in the C-Terminal Part of the Molecule with Naphthylalanine

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Prahl A. , Derdowska I. , Dawidowska O. , Neubert K. , Hartrodt B. , Wierzba T. , Juzwa W. , Lammek B.

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2002

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tom Vol. 76 / nr 10

1433-1439

EN

This paper describes the synthesis and some pharmacological properties of eight new analogues of a previously synthesized bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly- Thi-Ser-D-Phe-Thi-Arg. Two peptides were designed by substitution of Thi8 with L-1- and L-2-naphthylalanine. In two further analogues this modification was combined with placement in position 7 of D-2-naphthylalanine residue. Finally, we obtained four analogues by acylation of N-terminus of the peptides mentioned above with 1-adamantaneacetic acid. The activity of analogues was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin (rat blood pressure test). Our results indicate that the modification proposed decreased the B2 antagonistic activity, however, the range of this effect was different. We also observed that even minor changes in the structure of the C-terminal part of the B2 antagonists may significantly influence their activity.

4

New Bradykinin Analogues Modified in Position 6 and 7 with Naphthylalanine

63%

Prahl A. , Derdowska I. , Dawidowska O. , Neubert K. , Hartrodt B. , Wierzba T. , Juzwa W. , Lammek B.

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tom Vol. 77 / nr 7

881-887

EN

We describe the synthesis and some pharmacological properties of eight new analogues of a previously synthesized bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser- D-Phe-Thi-Arg. Two peptides were designed by substitution of Ser6 with L-1- and L-2-naphthylalanine. In two further analogues this modification was combined with placement in position 7 of D-naphthylalanine residue. We also obtained four analogues by acylation of N-terminus of the peptides mentioned above with 1-adamantaneacetic acid. The activity of analogues was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin (rat blood pressure test). Our results indicate that the modifications proposed decreased significantly the B2 antagonistic activity. Moreover, our earlier observation, suggesting that acylation of the N-terminus of many BK antagonists with bulky groups consistently improved the antagonistic potency, appears to be valid only for one pair of analogues.