title: Novel octreotide dicarba-analogues with high affinity and different selectivity for somatostatin receptors.
abstract: A limited set of novel octreotide dicarba-analogues with non-native aromatic side chains in positions 7 and/or 10 were synthesized. Their affinity toward the ssts1-5 was determined. Derivative 4 exhibited a pan-somatostatin activity, except sst4, and derivative 8 exhibited high affinity and selectivity toward sst5. Actually, compound 8 has similar sst5 affinity (IC50 4.9 nM) to SRIF-28 and octreotide. Structure-activity relationships suggest that the Z geometry of the double-bond bridge is that preferred by the receptors. The NMR study on the conformations of these compounds in SDS(-d25) micelles solution shows that all these analogues have the pharmacophore beta-turn spanning Xaa7-D-Trp8-Lys9-Yaa10 residues. Notably, the correlation between conformation families and affinity data strongly indicates that the sst5 selectivity is favored by a helical conformation involving the C-terminus triad, while a pan-SRIF mimic activity is based mainly on a conformational equilibrium between extended and folded conformational states.
authors.affiliation: Laboratory of Peptides & Proteins, Chemistry & Biology, Department of Chemistry Ugo Schiff, University of Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Cianni
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Karin
authors.initials: K
authors.lastname: Beetschen
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Papini
authors.forename: Mauro
authors.initials: M
authors.lastname: Ginanneschi
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D008968:Molecular Conformation; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012967:Sodium Dodecyl Sulfate; D013329:Structure-Activity Relationship
chemical_list: D008823:Micelles; D017481:Receptors, Somatostatin; D012967:Sodium Dodecyl Sulfate; D015282:Octreotide