Biological activity of parathyroid hormone antagonists substituted at position 13

Michael Chorev; Eliahu Roubini; Roberta L. McKee; Susan W. Gibbons; Jane E. Reagan; Mark E. Goldman; Michael P. Caulfield; Michael Rosenblatt

doi:10.1016/0196-9781(91)90167-N

Biological activity of parathyroid hormone antagonists substituted at position 13

Michael Chorev
, Eliahu Roubini
, Roberta L. McKee
, Susan W. Gibbons
, Jane E. Reagan
, Mark E. Goldman
, Michael P. Caulfield
, Michael Rosenblatt^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	57-62
Number of pages	6
Journal	Peptides
Volume	12
Issue number	1
DOIs	https://doi.org/10.1016/0196-9781(91)90167-N
State	Published - 1991

Keywords

Adenylate cyclase
Bovine renal cortical membranes
Human bone derived (B10) cells
Parathyroid hormone antagonists
Receptor binding
Solid-phase peptide synthesis

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10.1016/0196-9781(91)90167-N

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title = "Biological activity of parathyroid hormone antagonists substituted at position 13",

abstract = "Lysine occupies position 13 in the parathyroid hormone (PTH) antagonist, [Nle8,18,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 [Nle8,18,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[Nle8,18,D-Trp12,Lys13(ε\{lunate\}-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.",

keywords = "Adenylate cyclase, Bovine renal cortical membranes, Human bone derived (B10) cells, Parathyroid hormone antagonists, Receptor binding, Solid-phase peptide synthesis",

author = "Michael Chorev and Eliahu Roubini and McKee, \{Roberta L.\} and Gibbons, \{Susan W.\} and Reagan, \{Jane E.\} and Goldman, \{Mark E.\} and Caulfield, \{Michael P.\} and Michael Rosenblatt",

year = "1991",

doi = "10.1016/0196-9781(91)90167-N",

language = "אנגלית",

volume = "12",

pages = "57--62",

journal = "Peptides",

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number = "1",

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T1 - Biological activity of parathyroid hormone antagonists substituted at position 13

AU - Chorev, Michael

AU - Roubini, Eliahu

AU - McKee, Roberta L.

AU - Gibbons, Susan W.

AU - Reagan, Jane E.

AU - Goldman, Mark E.

AU - Caulfield, Michael P.

AU - Rosenblatt, Michael

PY - 1991

Y1 - 1991

N2 - Lysine occupies position 13 in the parathyroid hormone (PTH) antagonist, [Nle8,18,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 [Nle8,18,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[Nle8,18,D-Trp12,Lys13(ε{lunate}-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.

AB - Lysine occupies position 13 in the parathyroid hormone (PTH) antagonist, [Nle8,18,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 [Nle8,18,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[Nle8,18,D-Trp12,Lys13(ε{lunate}-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.

KW - Adenylate cyclase

KW - Bovine renal cortical membranes

KW - Human bone derived (B10) cells

KW - Parathyroid hormone antagonists

KW - Receptor binding

KW - Solid-phase peptide synthesis

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VL - 12

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JO - Peptides

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IS - 1

ER -

Biological activity of parathyroid hormone antagonists substituted at position 13

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