Biological activity of parathyroid hormone antagonists substituted at position 13

Abstract Lysine occupies position 13 in the parathyroid hormone (PTH) antagonist, [Nle 8,18 ,Tyr 34 ]bPTH(7–34)NH 2 . Acylation of the ϵ-amino group in lysine 13 by a hydrophobic moiety is well tolerated in terms of bioactivity: the analog [Nle 8,18 ,D-Trp 12 ,Lys 13 (ϵ-3-phenylpropanoyl), Tyr 34 ]bPTH(7–34)NH 2 is equivalent to the parent peptide in its affinity for PTH receptors and its ability to inhibit PTH-stimulated adenylate cyclase in both kidney- and bone-based assays. Truncation of this peptide by deletion of phenylalanyl 7 with concomitant removal of the amino-terminal α-amino group yielded the analog desamino[Nle 8,18 ,D-Trp 12 ,Lys 13 (ϵ-3-phenylpropanoyl), Tyr 34 ]bPTH(8–34)NH 2 , an antagonist of high potency in vitro ( K b = 4 and 9 nM, K i = 73 and 3.5 nM in kidney- and bone-based assays, respectively). Also this analog is potentially stable to aminopeptidases present in many biological systems.