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Cyclization by a Specific Lactam Increases the Ability of Human Parathyroid Hormone (hPTH)‐(1–31)NH 2 to Stimulate Bone Growth in Ovariectomized Rats
Author(s) -
Whitfield J. F.,
Morley P.,
Willick G.,
Langille R.,
Ross V.,
Maclean S.,
Barbier J.R.
Publication year - 1997
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.1997.12.8.1246
Subject(s) - medicine , endocrinology , parathyroid hormone , ovariectomized rat , chemistry , adenylyl cyclase , receptor , anabolism , parathyroid hormone receptor , estrogen , biology , hormone receptor , calcium , cancer , breast cancer
Human parathyroid hormone (hPTH)‐(1–31)NH 2 (Ostabolin), which only stimulates adenylyl cyclase (AC) instead of AC and phospholipase‐C as do hPTH(1–84) and hPTH(1–34), strongly stimulates femoral cortical and trabecular bone growth in ovariectomized (OVX) rats. Two side‐chain lactams have been introduced in the hydrophilic face of the receptor‐binding region of the fragment's Ser 17 ‐Val 31 amphiphilic α‐helix in an attempt to develop improved analogs for the treatment of osteoporosis. Replacing the polar Lys 27 with an apolar Leu on the hydrophobic face of this α‐helix and stabilizing the helix with a lactam between Glu 22 and Lys 26 produced a fragment, [Leu 27 ]‐cyclo(Glu 22 ‐Lys 26 )‐hPTH(1–31)NH 2 , which had six times the AC‐stimulating ability of hPTH(1–31)NH 2 in ROS 17/2 rat osteosarcoma cells, but the other helix‐stabilizing lactam derivative [Leu 27 ]‐cyclo(Lys 26 ‐Arg 30 )‐hPTH(1–31)NH 2 did not have a greater AC‐stimulating ability than hPTH(1–31)NH 2 , to stimulate AC in ROS 17/2 rat osteosarcoma cells. As expected from AC stimulation being responsible for PTH's anabolic action, [Leu 27 ]‐cyclo(Glu 22 ‐Lys 26 )‐hPTH(1–31)NH 2 was, depending on the experimental design, a 1.4 to 2 times better stimulator of trabecular bone growth in the OVX rat model than either hPTH(1–31)NH 2 or [Leu 27 ]‐cyclo(Lys 26 ‐Arg 30 )‐hPTH(1–31)NH 2 . Thus, there is now a more potently anabolic derivative of hPTH(1–31)NH 2 , [Leu 27 ]‐cyclo(Glu 22 ‐Lys 26 )‐hPTH(1–31)NH 2 , which might ultimately prove to be one of the more effective therapeutics for osteoporosis.