Ring size of somatostatin analogues (ODT-8) modulates receptor selectivity and binding affinity.
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).
Erchegyi
Judit
J
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.
Grace
Christy Rani R
CR
Samant
Manoj
M
Cescato
Renzo
R
Piccand
Veronique
V
Riek
Roland
R
Reubi
Jean Claude
JC
Rivier
Jean E
JE
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
D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C480605:cyclo(cysteinyl(3)-phenylalanyl(6)-phenylalanyl(7)-tryptophyl(8)-lysyl(9)-threonyl(10)-phenylalanyl(11)-cysteinyl(14))