PT  - JOURNAL ARTICLE
AU  - Sam R. J. Hoare
AU  - Ted B. Usdin
TI  - Tuberoinfundibular Peptide (7-39) [TIP(7-39)], a Novel, Selective, High-Affinity Antagonist for the Parathyroid Hormone-1 Receptor with No Detectable Agonist Activity
DP  - 2000 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 761--770
VI  - 295
IP  - 2
4099  - http://jpet.aspetjournals.org/content/295/2/761.short
4100  - http://jpet.aspetjournals.org/content/295/2/761.full
SO  - J Pharmacol Exp Ther2000 Nov 01; 295
AB  - 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 of125I-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 of125I-[Nle8,18,d-Trp12,Tyr34]bPTH(7-34) could not be detected. Kinetic analysis indicated that125I-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. U.S. Government