title: Novel sst5-selective somatostatin dicarba-analogues: synthesis and conformation-affinity relationships.
abstract: 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.
authors.affiliation: Laboratory of Peptides and Proteins, Chemistry and Biology, Department of Organic Chemistry, University of Firenze, Via Lastruccia 13 I-50019, Sesto Fiorentino, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: D'Addona
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Véronique
authors.initials: V
authors.lastname: Piccand
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Cianni
authors.forename: Francesca
authors.initials: F
authors.lastname: Gori
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Papini
authors.forename: Mauro
authors.initials: M
authors.lastname: Ginanneschi
mesh_terms: 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
chemical_list: D009842:Oligopeptides; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D012428:Ruthenium