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 lysine 13 by a hydrophobic moiety is well tolerated in terms of bioactivity: the analog [Nle8,18, D-Trp12,Lys 13 (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 (Kb = 4 and 9 nM, Ki = 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.
Chorev
M
M
Hebrew University of Jerusalem, Faculty of Medicine, Israel.
Roubini
E
E
McKee
R L
RL
Gibbons
S W
SW
Reagan
J E
JE
Goldman
M E
ME
Caulfield
M P
MP
Rosenblatt
M
M
D000215:Acylation; D000262:Adenylyl Cyclases / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D002417:Cattle; D006801:Humans; D008239:Lysine; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000032:analysis / Q000138:chemical synthesis; D011956:Receptors, Cell Surface / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone; D013329:Structure-Activity Relationship
D010281:Parathyroid Hormone; D010455:Peptides; D011956:Receptors, Cell Surface; D018016:Receptors, Parathyroid Hormone; D000262:Adenylyl Cyclases; D008239:Lysine