BIOLOGICAL-ACTIVITY OF PARATHYROID-HORMONE ANTAGONISTS SUBSTITUTED AT POSITION-13

Lysine occupies position 13 in the parathyroid hormone (PTH) antagonist, [Nle8.18,Tyr34]bPTH(7-34)NH2. Acylation of the epsilon-amino group in lysine13 by a hydrophobic moiety is well tolerated in terms of bioactivity: the analog [Nle8.18,D-Trp12,Lys13(epsilon-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 alpha-amino group yielded the analog desamino[Nle8.18,D-Trp12,Lys13(epsilon-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.