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Vol. 295, Issue 2, 761-770, November 2000
Unit on Cell Biology, Laboratory of Genetics, National Institute of
Mental Health, Bethesda, Maryland
The parathyroid hormone (PTH)-1 receptor mediates the
pathophysiological effects of PTH in hyperparathyroidism and
PTH-related protein (PTHrP) in humoral hypercalcemia of malignancy. A
PTH1 receptor antagonist may be of therapeutic utility in these
disorders. We recently identified a novel antagonist,
tuberoinfundibular peptide (7-39) [TIP(7-39)], derived from the
likely endogenous ligand for the PTH2 receptor TIP39. In this study its
in vitro profile is evaluated and compared with that of
[D-Trp12,Tyr34]bPTH(7-34)
and PTHrP(7-34), representing the two previously known structural
classes of PTH1 receptor antagonists. TIP(7-39) binds with higher
affinity (6.2 nM) to the PTH1 receptor than
[D-Trp12,Tyr34]bPTH(7-34) (45 nM)
and PTHrP(7-34) (65 nM) and displays a 5.5-fold greater PTH1/PTH2
receptor selectivity. TIP(7-39) does not stimulate cAMP accumulation
via the PTH1 receptor [in a sensitive assay that detects the activity
of the weak partial agonist
[Nle8,18,Tyr34]bPTH(3-34)] and does not
increase intracellular calcium. Schild analysis for TIP(7-39) was
consistent with purely competitive antagonism of PTH(1-34)'s
stimulation of cAMP accumulation (slope = 0.99 ± 0.24). The
pKB for TIP(7-39) (7.1 ± 0.3) was
higher than that for
[D-Trp12,Tyr34]bPTH(7-34)
(6.5 ± 0.0) and PTHrP(7-34) (6.0 ± 0.1). Binding of 125I-TIP(7-39) to the PTH1 receptor could be measured
(KD = 1.3 ± 0.1 nM,
Bmax = 1.3 ± 0.1 pmol/mg),
whereas binding of
125I-[Nle8,18,D-Trp12,Tyr34]bPTH(7-34)
could not be detected. Kinetic analysis indicated that
125I-TIP(7-39) dissociates much more slowly
(t1/2 = 14 min) than [D-Trp12,Tyr34]bPTH(7-34) (13 s)
and PTHrP(7-34) (9 s). The novel antagonist TIP(7-39) therefore
displays a more favorable in vitro pharmacological profile than
antagonists derived from PTH and PTHrP and may be useful for
demonstrating the utility of PTH1 receptor antagonism in the treatment
of hypercalcemia.
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