title: N-imidazolebenzyl-histidine substitution in somatostatin and in its octapeptide analogue modulates receptor selectivity and function.
abstract: Despite 3 decades of focused chemical, biological, structural, and clinical developments, unusual properties of somatostatin (SRIF, 1) analogues are still being uncovered. Here we report the unexpected functional properties of 1 and the octapeptide cyclo(3-14)H-Cys-Phe-Phe-Trp(8)-Lys-Thr-Phe-Cys-OH (somatostatin numbering; OLT-8, 9) substituted by imBzl-l- or -d-His at position 8. These analogues were tested for their binding affinity to the five human somatostatin receptors (sst(1-5)), as well as for their functional properties (or functionalities) in an sst(3) internalization assay and in an sst(3) luciferase reporter gene assay. While substitution of Trp(8) in somatostatin by imBzl-l- or -d-His(8) results in sst(3) selectivity, substitution of Trp(8) in the octapeptide 9 by imBzl-l- or -d-His(8) results in loss of binding affinity for sst(1,2,4,5) and a radical functional switch from agonist to antagonist.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Jean E
authors.initials: JE
authors.lastname: Rivier
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
mesh_terms: D002478:Cells, Cultured; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D006639:Histidine; D013004:Somatostatin; D008156:Luciferases