title: N-terminal truncation of salmon calcitonin leads to calcitonin antagonists. Structure activity relationship of N-terminally truncated salmon calcitonin fragments in vitro and in vivo.
abstract: Structural requirements for binding to the bone calcitonin (CT) receptor and for CT bioactivity both in vitro and in vivo were assessed for a series of N-terminally truncated, N alpha-acetylated, fragments of salmon calcitonin (sCT). Sequential deletion of amino acid residues from the amino-terminus of [Ala7]sCT-(2-32) peptide amide first led to partial agonists and, upon deletion of residues 1 to 7, to a high affinity antagonist, N alpha-acetyl-sCT-(8-32)-NH2. The presence of two separate domains within the sCT sequence is proposed: (I) a binding domain comprising residues 9-32 and (II) an activation domain requiring residues 3 to 6. N alpha-acetyl-sCT-(8-32)-NH2, in several bioassays including plasminogen activator release from LLC-PK1 cells (pA2 = 7.31), cAMP production in UMR-106-06 cells (pA2 = 7.81) and in the fetal rat long bone resorption assay showed potent antagonistic properties.
authors.affiliation: Sandoz Pharma Ltd, Basel, Switzerland.
authors.forename: J H
authors.initials: JH
authors.lastname: Feyen
authors.forename: F
authors.initials: F
authors.lastname: Cardinaux
authors.forename: R
authors.initials: R
authors.lastname: Gamse
authors.forename: C
authors.initials: C
authors.lastname: Bruns
authors.forename: M
authors.initials: M
authors.lastname: Azria
authors.forename: U
authors.initials: U
authors.lastname: Trechsel
mesh_terms: D000107:Acetylation; D000818:Animals; D001862:Bone Resorption; D002116:Calcitonin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D012516:Osteosarcoma / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D010446:Peptide Fragments; C028815:salmon calcitonin; D002116:Calcitonin; D000242:Cyclic AMP; D010960:Plasminogen Activators