Novel sst5-selective somatostatin dicarba-analogues: synthesis and conformation-affinity relationships.
We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst 1-5) 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 (1)H NMR spectroscopy. Conformation-affinity relationships confirmed the importance of D-Phe(2) 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 3(10)-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.
D'Addona
Debora
D
Laboratory of Peptides and Proteins, Chemistry and Biology, Department of Organic Chemistry, University of Firenze, Via Lastruccia 13 I-50019, Sesto Fiorentino, Italy.
Carotenuto
Alfonso
A
Novellino
Ettore
E
Piccand
Véronique
V
Reubi
Jean Claude
JC
Di Cianni
Alessandra
A
Gori
Francesca
F
Papini
Anna Maria
AM
Ginanneschi
Mauro
M
D000818:Animals; D002384:Catalysis; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012428:Ruthenium; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D012428:Ruthenium