CYCLIZATION BY A SPECIFIC LACTAM INCREASES THE ABILITY OF HUMAN PARATHYROID-HORMONE (HPTH)-(1-31)NH2 TO STIMULATE BONE-GROWTH IN OVARIECTOMIZED RATS

Human parathyroid hormone (hPTH)-(131)NH2 (Ostabolin), which only stim ulates adenylyl cyclase (AC) instead of AC and phospholipase-C as do h PTH(1-84) and hPTH(134), strongly stimulates femoral cortical and trab ecular bone growth in ovariectomized (OVX) rats, Two side-chain lactam s have been introduced in the hydrophilic face of the receptor-binding region of the fragment's Ser(17)-Val-(31) amphiphilic alpha-helix in an attempt to develop improved analogs for the treatment of osteoporos is, Replacing the polar Lys(27) with an apolar Leu on the hydrophobic face of this alpha-helix and stabilizing the helix with a lactam betwe en Glu(22) and Lys(26) produced a fragment, [Leu(27)]-cyclo(Glu(22)-Ly s(26))-hPTH(1-31)NH2, which had six times the AC-stimulating ability o f hPTH(1-31)NH2 in ROS 17/2 rat osteosarcoma cells, but the other heli x-stabilizing lactam derivative [Leu(27)]-cyclo(Lys(26)-Arg(30))-hPTH( 1-31)NH2 did not have a greater AC-stimulating ability than hPTH(1-31) NH2, to stimulate AC in ROS 17/2 rat osteosarcoma cells, As expected f rom AC stimulation being responsible for PTH's anabolic action, [Leu(2 7)]-cyclo(Glu(22)-Lys(26))-hPTH(131)NH2 was, depending on the experime ntal design, a 1.4 to 2 times better stimulator of trabecular bone gro wth in the OVX rat model than either hPTH(1-31)NH2 or [Leu(27)]-cyclo( Lys(26)-Arg(30))-hPTH(1-31)NH2. Thus, there is now a more potently ana bolic derivative of hPTH(1-31)NH2, [Leu(27)]-cyclo(Gln(22)-Lys(26))-hP TH(1-31)NH2, which might ultimately prove to be one of the more effect ive therapeutics for osteoporosis.