title: 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) greater than nle bPTH-(1-34) greater than bPTH-(1-84) much greater than TAbPTH-(1-34). Nle bPTH-(3-34) and bPTH-(7-34) did not affect cAMP formation in intact cells at concentrations up to 10 microM. The rank order of potency for the inhibition of phosphate transport was bPTH-(1-34) = hPTHrP-(1-34) greater than nle bPTH-(1-34) greater than bPTH-(1-84) = TAbPTH-(1-34) greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, University of Missouri, Columbia.
authors.forename: J A
authors.initials: JA
authors.lastname: Cole
authors.forename: D L
authors.initials: DL
authors.lastname: Carnes
authors.forename: L R
authors.initials: LR
authors.lastname: Forte
authors.forename: S
authors.initials: S
authors.lastname: Eber
authors.forename: R E
authors.initials: RE
authors.lastname: Poelling
authors.forename: P K
authors.initials: PK
authors.lastname: Thorne
mesh_terms: D000586:Amination; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009893:Opossums; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010710:Phosphates / Q000493:pharmacokinetics; D012964:Sodium / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010710:Phosphates; C058350:parathyroid hormone (7-34); C025076:parathyroid hormone (1-34), bovine; C031617:parathyroid hormone (3-34); D012964:Sodium; D000242:Cyclic AMP