Biological activity of parathyroid hormone antagonists substituted at position 13

Lysine occupies position 13 in the parathyroid hormone (PTH) antagonist, [Nle^8,18,Tyr³⁴]bPTH(7-34)NH₂. Acylation of the ε{lunate}-amino group in lysine¹³ by a hydrophobic moiety is well tolerated in terms of bioactivity: the analog [Nle^8,18,D-Trp¹²,Lys¹³(ε{lunate}-3-phenylpropanoyl), Tyr³⁴]bPTH(7-34)NH₂ 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 phenylalanyl⁷ with concomitant removal of the amino-terminal α-amino group yielded the analog desamino[Nle^8,18,D-Trp¹²,Lys¹³(ε{lunate}-3-phenylpropanoyl), Tyr³⁴]bPTH(8-34)NH₂, 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.