title: Ring size of somatostatin analogues (ODT-8) modulates receptor selectivity and binding affinity.
abstract: The synthesis, biological testing, and NMR studies of several analogues of H-c[Cys (3)-Phe (6)-Phe (7)-DTrp (8)-Lys (9)-Thr (10)-Phe (11)-Cys (14)]-OH (ODT-8, a pan-somatostatin analogue, 1) have been performed to assess the effect of changing the stereochemistry and the number of atoms in the disulfide bridge on binding affinity. Cysteine at positions 3 and/or 14 (somatostatin numbering) were/was substituted with d-cysteine, norcysteine, D-norcysteine, homocysteine, and/or D-homocysteine. The 3D structure analysis of selected partially selective, bioactive analogues (3, 18, 19, and 21) was carried out in dimethylsulfoxide. Interestingly and not unexpectedly, the 3D structures of these analogues comprised the pharmacophore for which the analogues had the highest binding affinities (i.e., sst 4 in all cases).
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology and Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.forename: Christy Rani R
authors.initials: CR
authors.lastname: Grace
authors.forename: Manoj
authors.initials: M
authors.lastname: Samant
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Veronique
authors.initials: V
authors.lastname: Piccand
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Jean E
authors.initials: JE
authors.lastname: Rivier
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C480605:cyclo(cysteinyl(3)-phenylalanyl(6)-phenylalanyl(7)-tryptophyl(8)-lysyl(9)-threonyl(10)-phenylalanyl(11)-cysteinyl(14))