Analogues of Human Parathyroid Hormone (1–31)NH 2: Further Evaluation of the Effect of Conformational Constraint on Biological Activity

Abstract

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=0.29 nM). 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.