title: Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units.
abstract: Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH(2)) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity.
authors.affiliation: Department of Organic Chemistry, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gazal
authors.forename: Garry
authors.initials: G
authors.lastname: Gelerman
authors.forename: Ofer
authors.initials: O
authors.lastname: Ziv
authors.forename: Olga
authors.initials: O
authors.lastname: Karpov
authors.forename: Pninit
authors.initials: P
authors.lastname: Litman
authors.forename: Moshe
authors.initials: M
authors.lastname: Bracha
authors.forename: Michel
authors.initials: M
authors.lastname: Afargan
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D004220:Disulfides / Q000737:chemistry*; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004220:Disulfides; C420459:PTR 3173; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D013004:Somatostatin