Analogues of human parathyroid hormone (1-31)NH(2): further evaluation of the effect of conformational constraint on biological activity

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 3; pp. 731 - 736
• Main Authors: Condon, Stephen M, Darnbrough, Shelley, Burns, Christopher J, Bobko, Mark A, Morize, Isabelle, Uhl, Joanne, Jariwala, Navinchandra U, Burke, Kathleen, Labaudiniere, Richard F
• Format: Journal Article
• Language: English
• Published: England 01.03.2002
• Subjects: Adenylyl Cyclases - drug effects; Amino Acid Sequence; Animals; Humans; Lactams - chemistry; Molecular Sequence Data; Parathyroid Hormone - chemistry; Parathyroid Hormone - genetics; Parathyroid Hormone - pharmacology; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Protein Binding; Protein Conformation; Protein Engineering; Rats; Receptors, Parathyroid Hormone - agonists; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0968-0896

A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.