Structure‐activity relationships of parathyroid hormone analogs in the opossum kidney cell line

Abstract

Structural alterations in the parathyroid hormone (PTH) molecule produce marked changes in biologic activity. We examined the relative sensitivity of PTH‐stimulated cAMP formation and PTH‐inhibitable Na+‐ dependent phosphate transport responses to bovine PTH analogs [bPTH‐(1–34), bPTH‐(1–84), 8,18‐norleucine‐34‐tyrosinamide bPTH‐(1‐34), bPTH‐(7–34)‐amide, 8,18‐norleucine‐34‐tyrosinamide bPTH‐(3–34), transaminated bPTH‐(1–34)] and the human PTH‐related peptide of malignancy (1–34) in cultured opossum kidney cells. The rank order of potency for stimulation of cAMP formation was bPTH‐(1–34) = hPTHrP‐(1–34) > nle bPTH‐(1–34) > bPTH‐(1–84) ≥ TAbPTH‐(1–34). Nle bPTH‐(3–34) and bPTH‐(7–34) did not affect cAMP formation in intact cells at concentrations up to 10 μM. The rank order of potency for the inhibition of phosphate transport was bPTH‐(1–34) = hPTHrP‐(1–34) > nle bPTH‐(1–34) > bPTH‐(1–84) = TAbPTH‐(1–34) > nle bPTH‐(3–34). TAbPTH‐(1–34) was a full agonist and inhibited phosphate transport at concentrations that did not increase cAMP formation, but nle bPTH‐(3–34) was a partial agonist in spite of its inability to stimulate cAMP formation. Bovine PTH‐(7–34) had no effect on phosphate transport. This study indicates that changes in the PTH molecule produce analogs that apparently discriminate between the cAMP‐stimulating activity and phosphate transport‐inhibiting activities of the native hormone. These analogs may prove useful in defining PTH receptor subtypes based on differences in their pharmacologic properties in the regulation of physiologic responses in PTH target cells. Copyright © 1989 ASBMR

Publication Title

Journal of Bone and Mineral Research

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