Novel sst5-Selective Somatostatin Dicarba-Analogues: Synthesis and Conformation−Affinity Relationships
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- 作者：Debora D’ ; Addona ; Alfonso Carotenuto ; Ettore Novellino ; Vé ; ronique Piccand ; Jean Claude Reubi ; Alessandra Di Cianni ; Francesca Gori ; Anna Maria Papini ; Mauro Ginanneschi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：February 14, 2008
- 年：2008
- 卷：51
- 期：3
- 页码：512 - 520
- 全文大小：945K
- 年卷期：v.51,no.3(February 14, 2008)
- ISSN：1520-4804
文摘
We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst1–5) of a few analogues of the cyclic octapeptide octreotide (1), where the disulfide bridge was replaced by a dicarba group. These analogues were prepared by on-resin RCM of linear hepta-peptides containing two allylglycine residues; first- and second-generation Grubbs catalyst efficiencies were compared. The C
C bridge was hydrogenated via two different methods. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by 1H NMR spectroscopy. Conformation−affinity relationships confirmed the importance of D-Phe2 orientation for sst2 affinity. Moreover, helical propensities well correlates with the peptide sst5 affinity. The presence of the bulky aromatic side chain of Tyr(Bzl)10 favored the formation of a 310-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.
C bridge was hydrogenated via two different methods. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by 1H NMR spectroscopy. Conformation−affinity relationships confirmed the importance of D-Phe2 orientation for sst2 affinity. Moreover, helical propensities well correlates with the peptide sst5 affinity. The presence of the bulky aromatic side chain of Tyr(Bzl)10 favored the formation of a 310-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.