부산대학교 도서관

Human parathyroid hormone (hPTH)‐(1–31)NH2(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 Ser17‐Val31amphiphilic α‐helix in an attempt to develop improved analogs for the treatment of osteoporosis. Replacing the polar Lys27with an apolar Leu on the hydrophobic face of this α‐helix and stabilizing the helix with a lactam between Glu22and Lys26produced a fragment, [Leu27]‐cyclo(Glu22‐Lys26)‐hPTH(1–31)NH2, which had six times the AC‐stimulating ability of hPTH(1–31)NH2in ROS 17/2 rat osteosarcoma cells, but the other helix‐stabilizing lactam derivative [Leu27]‐cyclo(Lys26‐Arg30)‐hPTH(1–31)NH2did not have a greater AC‐stimulating ability than hPTH(1–31)NH2, to stimulate AC in ROS 17/2 rat osteosarcoma cells. As expected from AC stimulation being responsible for PTH's anabolic action, [Leu27]‐cyclo(Glu22‐Lys26)‐hPTH(1–31)NH2was, 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)NH2or [Leu27]‐cyclo(Lys26‐Arg30)‐hPTH(1–31)NH2. Thus, there is now a more potently anabolic derivative of hPTH(1–31)NH2, [Leu27]‐cyclo(Glu22‐Lys26)‐hPTH(1–31)NH2, which might ultimately prove to be one of the more effective therapeutics for osteoporosis.