Synthesis, activity on NK-3 tachykinin receptor and conformational solution studies of scyliorhinin II analogs modified at position 16.
Two analogs of a tachykinin family peptides - scyliorhinin II (ScyII): [Aib(16)]ScyII and [Sar(16)]ScyII were synthesized by the solid-phase method using Fmoc chemistry. Conformational studies in water and DMSO-d(6) on these peptides were performed using a combination of two-dimensional NMR and theoretical conformational analysis. The solution structure of the peptides studied is interpreted as an equilibrium of several conformers with different statistical weights. The structure of [Sar(16)]ScyII in water appeared to be more flexible, especially in the C-terminal fragment. A better defined structure for this analog was obtained in DMSO-d(6), in which the analysis resulted in a family of conformers with similar shapes. Some of these conformers were characterized by the presence of a 3(10)-helix in the N-terminal fragment and middle part of the molecule. The introduction of the Aib residue in position 16 significantly rigidifies the structure. For [Aib(16)]ScyII in both solvent systems very similar populations of conformations were obtained which are characterized by the presence of a 3(10)-helix in the 13-18 fragment. A common structural motif was found in conformationally constrained Cys(7)-Cys(13) fragment, which resembles the Greek letter 'omega'. The differences in the solution structure of the C-terminal fragment of the peptides studied are responsible for their specificity. [Aib(16)]ScyII showed 25% the agonistic activity of selective NK-3 agonist - senktide, but it also showed antagonist effect vs. this peptide, whereas [Sar(16)]ScyII appeared to be a full agonist of NK-3 tachykinin receptor.
Rodziewicz-Motowidło
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S
Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
Lesner
A
A
Łegowska
A
A
Czaplewski
C
C
Liwo
A
A
Rolka
K
K
Patacchini
R
R
Quartara
L
L
D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D018042:Receptors, Neurokinin-3 / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015320:Tachykinins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D018042:Receptors, Neurokinin-3; D015320:Tachykinins; C048919:scyliorhinin II