The effect of monocyclic and bicyclic analogs of human parathyroid hormone(hPTH)-(1-31)NH2 on bone formation and mechanical strength in ovariectomized rats

The [Leu(27)]cyclo(Glu(22)-Lys(26))-hPTH-(1-31)NH(2)lactam is a stronger st imulator of adenylyl cyclase activity and a better stimulator of trabecular bone in the ovariectomized (OVX) rat model of osteopenia than hPTH-(1-31)N H2. This enhanced activity is due in large part to the stabilization of the amphiphilic receptor-binding ct-helix in the Ser(17)-Gln(29) region. The g oal of the present study was to determine whether further cyclization could produce a more active hPTH analog. To this end, we compared the relative b ioactivities of the bicyclic hPTH analog [Glu(17) ,Leu(27)]cyclo(Lys(13)-Gl u(17),Glu(22)-Lys(26))-hPTH-(1-31)NH2, made by replacing Ser(17) with Glu(1 7) and introducing a second lactam linkage between Lys(13) and Glu(17). The relative EC50 for adenylyl cyclase stimulation by the bicyclic hPTH analog was similar to the EC50 of the monocyclic [Leu(27)]cyclo(Glu(22)-Lys(26))- hPTH-(1-31)NH2, but the bicyclic analog was still more active than hPTH-(1- 31)NH2. As expected from adenylyl cyclase stimulation being responsible for PTH's anabolic action, the bicyclic hPTH analog [Glu(17), Leu(27)]cyclo(Ly s(13)-Glu(17), Glu(22)-Lys(26))-hPTH-(1 -31)NH2 was able to increase femora l trabecular volume and thickness and mechanical strength in OVX rats, but it was no more effective than [Leu]cyclo(Glu(22)-Lys(26))-hPTH(1-31)NH2 whe n injected once daily in a dose of 0.8 nmol/100 g body weight. Thus, furthe r constraint of the conformation of hPTH-(1-31)NH2 by introducing two lacta m linkages between Lys(13)-Glu(17) and Glu(22)-Lys(26) did not raise the os teogenicity above that of the monocyclic analog.