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 CdC 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.

Novel sst5-Selective Somatostatin Dicarba-Analogues: Synthesis and Conformation-Affinity Relationships / D. D’Addona; A. Carotenuto; E. Novellino; V. Piccand; J.C. Reubi; A. Di Cianni; F. Gori; A.M. Papini; M. Ginanneschi. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 51:(2008), pp. 512-520. [10.1021/jm070886i]

Novel sst5-Selective Somatostatin Dicarba-Analogues: Synthesis and Conformation-Affinity Relationships

D. D’Addona;DI CIANNI, ALESSANDRA;F. Gori;PAPINI, ANNA MARIA;M. Ginanneschi
2008

Abstract

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 CdC 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.
2008
51
512
520
D. D’Addona; A. Carotenuto; E. Novellino; V. Piccand; J.C. Reubi; A. Di Cianni; F. Gori; A.M. Papini; M. Ginanneschi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/404157
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