Synthesis, activity on NK-3 tachykinin receptor and conformational solution studies of scyliorhinin II analogs modified at position 16

• Published in: The journal of peptide research 2001-08, Vol.58 (2), p.159-172
• Main Authors: Rodziewicz-Motowidło, S., Lesner, A., Łęgowska, A., Czaplewski, C., Liwo, A., Rolka, K., Patacchini, R., Quartara, L.
• Format: Article
• Language: English
• Subjects: Animals; conformational studies; GPI activity; Guinea Pigs; Ileum - drug effects; Ileum - metabolism; Models, Molecular; NMR spectroscopy; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Receptors, Neurokinin-3 - agonists; Receptors, Neurokinin-3 - metabolism; scyliorhinin II analogs; solid-phase synthesis; Stereoisomerism; Structure-Activity Relationship; tachykinins; Tachykinins - chemical synthesis; Tachykinins - chemistry; Tachykinins - pharmacology
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1034/j.1399-3011.2001.00886.x

: Two analogs of a tachykinin family peptides – scyliorhinin II (ScyII): [Aib16]ScyII and [Sar16]ScyII were synthesized by the solid‐phase method using Fmoc chemistry. Conformational studies in water and DMSO‐d6 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 [Sar16]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‐d6, in which the analysis resulted in a family of conformers with similar shapes. Some of these conformers were characterized by the presence of a 310‐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 [Aib16]ScyII in both solvent systems very similar populations of conformations were obtained which are characterized by the presence of a 310‐helix in the 13–18 fragment. A common structural motif was found in conformationally constrained Cys7−Cys13 fragment, which resembles the Greek letter ‘ω’. The differences in the solution structure of the C‐terminal fragment of the peptides studied are responsible for their specificity. [Aib16]ScyII showed 25% the agonistic activity of selective NK‐3 agonist – senktide, but it also showed antagonist effect vs. this peptide, whereas [Sar16]ScyII appeared to be a full agonist of NK‐3 tachykinin receptor.