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 [Leu²⁷]cyclo(Glu²²-Lys²⁶)-hPTH-(1-31)NH₂ lactam is a stronger stimulator of adenylyl cyclase activity and a better stimulator of trabecular bone in the ovariectomized (OVX) rat model of osteopenia than hPTH-(1-31)NH₂. This enhanced activity is due in large part to the stabilization of the amphiphilic receptor-binding α-helix in the Ser¹⁷-Gln²⁹ region. The goal of the present study was to determine whether further cyclization could produce a more active hPTH analog. To this end, we compared the relative bioactivities of the bicyclic hPTH analog [Glu¹⁷,Leu²⁷]cyclo(Lys¹³-Glu¹⁷,Glu²²-Lys²⁶)-hPTH-(1-31)NH₂, made by replacing Ser¹⁷ with Glu¹⁷ and introducing a second lactam linkage between Lys¹³ and Glu¹⁷. The relative EC₅₀ for adenylyl cyclase stimulation by the bicyclic hPTH analog was similar to the EC₅₀ of the monocyclic [Leu²⁷]cyclo(Glu²²-Lys²⁶)-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 [Glu¹⁷, Leu²⁷]cyclo(Lys¹³-Glu¹⁷, Glu²²-Lys²⁶)-hPTH-(1-31)NH₂ was able to increase femoral trabecular volume and thickness and mechanical strength in OVX rats, but it was no more effective than [Leu²⁷]cyclo(Glu²²-Lys²⁶)-hPTH-(1-31)NH₂ when injected once daily in a dose of 0.8 nmol/100 g body weight. Thus, further constraint of the conformation of hPTH-(1-31)NH₂ by introducing two lactam linkages between Lys¹³-Glu¹⁷ and Glu²²-Lys²⁶ did not raise the osteogenicity above that of the monocyclic analog.