Specificity and stability of a new PTH1 receptor antagonist, mouse TIP(7-39).

Abstract Parathyroid hormone 1 (PTH1) receptor antagonists might be of benefit in hypercalcemia of malignancy (HHM) and hyperparathyroidism. We previously identified bovine tuberoinfundibular peptide (7–39) (bTIP(7–39)) as a high-affinity PTH1 receptor antagonist. Mouse TIP(7–39) is an antagonist (rPTH1 K B =44 nM, rPTH2=940 nM) that is more potent than other known PTH1 receptor antagonists: bTIP(7–39) (210 nM), PTH-related protein (PTHrP)(7–34) (640 nM), and bPTH(7–34) (>3000 nM). Plasma proteases slowly ( t 1/2 =81 min) inactivated [ 125 I ]mTIP(7–39). Intravenous plasma [ 125 I ]mTIP(7–39) was bi-phasically cleared (radioactivity t 1/2 =2.9 min (70%) and 120 min (30%), binding activity t 1/2 =3.6 min (92%), and t 1/2 =21 min (8%)). Loss of unlabeled mTIP(7–39) (250 μg/kg i.v.) receptor binding was similar. mTIP(7–39)’s high-affinity should facilitate animal evaluation of effects of PTH1 receptor antagonism.