Abstract |
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 alpha-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 link-ages between Lys13-Glu17 and Glu22-Lys26 did not raise the osteogenicity above that of the monocyclic analog.
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Authors | P Morley, J F Whitfield, G E Willick, V Ross, S MacLean, J R Barbier, R J Isaacs, T T Andreassen |
Journal | Calcified tissue international
(Calcif Tissue Int)
Vol. 68
Issue 2
Pg. 95-101
(Feb 2001)
ISSN: 0171-967X [Print] United States |
PMID | 11310353
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Parathyroid Hormone
- Peptide Fragments
- parathyroid hormone (1-31)amide, human
- Adenylyl Cyclases
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Topics |
- Adenylyl Cyclases
(biosynthesis)
- Animals
- Bone Development
(drug effects, physiology)
- Bone Diseases, Metabolic
(drug therapy, etiology)
- Cyclization
- Elasticity
(drug effects)
- Female
- Femur
(drug effects, pathology, physiopathology)
- Lumbar Vertebrae
(drug effects, pathology, physiopathology)
- Ovariectomy
- Parathyroid Hormone
(chemistry, pharmacology, therapeutic use)
- Peptide Fragments
(chemistry, pharmacology, therapeutic use)
- Rats
- Rats, Sprague-Dawley
- Stress, Mechanical
- Structure-Activity Relationship
- Tumor Cells, Cultured
(drug effects, enzymology)
- Weight-Bearing
(physiology)
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