[Cyclic analogs of substance P. III. Cyclo (6(sup)gamma----oligomethylenediamine----11) substance P(6-11)-hexapeptides]. / Tsiklicheskie analogi veshchestva P. III. Cyclo(6(sup)gamma----oligometilendiamin----11) veshchestvo P(6-11)-geksapeptidy.

Cyclic analogues of substance P of the formula cyclo-[Glu-Phe-Phe-Gly-Leu-Met-NH(CH2)nNH-], where n = 3-10, 12, and open-chain analogues (XVIIIa, b) H-Glu.(NHR)-Phe-Phe-Gly-Leu-Met-NHR, where R = -CH3, -CH2CH2CH3, were synthesized. By NMR spectroscopy it was found that cyclo-compounds with n = 3-8 have regularly arranged structures, stabilized by intramolecular hydrogen bonds. Substances of this type showed less than or equal to 0.1% of the substance P activity on the guinea pig ileum, but some of them antagonize the natural peptide (for compound with n = 5 IC50 = 3.2.10(-6) M). The open-chain compounds proved to have rather high myotropic activity, viz., 22% (R = -CH3) and 8% (R = -CH2CH2CH3) of the substance P activity.

[Conformation of D-Orn2-containing cycloanalogs of enkephalins in dimethylsulfoxide solution]. / Prostranstvennaia struktura D-Orn2-soderzhashchikh tsikloanalogov énkefalina v rastvore dimetilsul'foksida.

The sterically acceptable structures of cyclo(2 delta----5)[D-Orn2, Pro5]- and cyclo(2 delta----5)[D-Orn2, Leu5]enkephalin (CE1 and CE2) consistent with NMR data including coupling constants, temperature dependencies of chemical shifts for amide protons and NOE values have been found by use of energy calculations in terms of rigid valence geometry and refined by the MM2 procedure. It has been shown that the major trans-isomer (with respect to Phe4-Pro5 bond) of CE1 in solution corresponds only to the FD*F*AA type of peptide backbone, and the minor cis-isomer of CE1 corresponds only to the FE*D*DF type. The less conformationally rigid CE2 analogue apparently exists in solution in the dynamic conformational equilibrium with preference of FD*C*AA type of the backbone structure. The obtained data on CE1 and CE2 space structures have been used for interpretating results of their biological testing.

[Determination of interproton distances in peptides by two-dimensional nuclear Overhauser effect spectroscopy (NOESY). Conformation of a cyclic analog of substance P in a solution]. / Opredelenie mezhprotonnykh rasstoianii v peptidakh metodom dvumernoi spektroskopii iadernogo éffekta Overkhauzera (NOESY). Konformatsiia tsiklicheskogo analoga "veshchestva P" v rastvore.

Quantitative method is developed for evaluation interproton distances in peptides in solution. The method is based on the measurement of the relative intensities of the cross-peaks in the pure-phase absorption NOESY spectra. The ratios of the cross-peak intensities IN alpha/I alpha N and INN/I alpha N enable to determine the corresponding interproton distances dN alpha, d alpha N and dNN for several amino acid residues. These distances can be used to estimate other distances with cross-peaks in NOESY spectra. As example, the interproton distances are determined in a cyclic hexapeptide, namely cyclic analogue of substance P: cyclo [H-Glu-Phe-Phe-Gly-Leu-Met-NH(CH2)3-NH-]. The spatial structure of the molecule in dimethylsulphoxide solution is established.

[Interpretation of 1H-NMR spectra of the cyclic analog of kallidin in solutions]. / Interpretatsiia spektrov 1H-IaMR tsiklicheskogo analoga kallidina v rastvorakh.

1H-NMR resonances of [cyclo (10-1 epsilon)]kallidin (cyclo-KL) in (CD3)2SO and H2O have been assigned by combined analysis of two-dimensional phase-sensitive COSY and NOESY spectra. The presence of three slowly interchangeable conformers cyclo-KL I, cyclo-KL II, and cyclo-KL III, has been established, their population in (CD3)2SO being 25, 35 and 40%, respectively. Cyclo-KL I conformer possesses trans-configuration of all peptide bonds, but in the cyclo-KL II and cyclo-KL III conformers the Pro3-Pro4 and Arg2-Pro3 peptide bonds, respectively, have cis-configuration. In----solution, the following exchange occurs between the conformers: cyclo-KL II----cyclo-KL I----cyclo-KL III. The assignment of 1H-NMR signals of all the three cyclo-KL conformers has been carried out in H2O by gradual titration with (CO3)2SO. The conformer populations in H2O are 45, 25 and 30%, respectively.

[Study of bradykinin conformation in a dimethylsulfoxide solution by two-dimensional 1H-NMR spectroscopy]. / Issledovanie konformatsionnogo sostoianiia bradikinina v rastvore dimetilsul'foksida metodami dvumernoi spektroskopii 1H-IaMR.

The role of charged groups of the nonapeptide bradykinin in stabilization of its spatial structure in dimethyl sulfoxide solution was investigated. The signal assignment in the 1H-NMR spectra was achieved by means of two dimensional correlated spectroscopy (COSY) and nuclear Overhauser enhancement spectroscopy (NOESY). The changes in the NH and C alpha H proton chemical shifts of the Arg1 and Arg9 residues, variations both in temperature coefficients of chemical shifts of NH-resonances and coupling constants, as well as the appearance of additional NOE cross-peaks in NOESY spectra for d alpha N and d beta N 1H-1H distances were revealed by comparing the NMR spectra for two states--with the protonated C-terminal carboxyl group and deprotonated one. The experimental results are in agreement with the assumption that the conformation of the peptide in (CD3)2SO is stabilized by electrostatic interaction between the oppositely charged N- and C-terminal groups. The conformation with deprotonated alpha-carboxyl group is characterized by two beta-turns in the sequences Pro2-Pro-Gly-Phe5 and Ser6-Pro-Phe-Arg9.

[Study of the spatial structure of a cyclic analog of bradykinin in solution by two-dimensional NMR spectroscopy]. / Issledovanie prostranstvennoi struktury tsiklicheskogo analoga bradikinina v rastvore metodami dvumernoi spektroskopii IaMR.

H NMR resonances of [cyclo (9----18) Lys1, Gly6]bradykinin (CBK) in (CD3)2SO and H2O solution have been assigned by combined analysis of two-dimensional COSY and NOESY spectra. The presence of two slowly interchangeable conformers of CBK in (CD3)2SO is established, the minor conformer not exceeding 15% in the population. The minor conformer is absent from the aqueous solution, chemical shifts of the CBK and bradykinin NH and C alpha H protons differ insignificantly. The major CBK conformer contains at least two X-Pro trans-peptide groups and three amide protons NH Phe5, NH Arg9 and N zeta H Lys1 protected from solvent. A system of cross-peaks from the NOESY spectra of CBK in (CD3)2SO has been analysed and the maximum distance between backbone protons and neighbouring amino acid residues evaluated. The experimental data agree well with the assumed type II beta-bend in the sequence Pro2-Pro3-Gly4-Phe5. Spatial structure models for the backbone fragment 6-9 of CBK containing two intramolecular hydrogen bonds that involve the NH Arg9 and N zeta H Lys1 protons and the carbonyl groups of Phe5 and Gly4 are proposed.