PTH2 and PTH1 Receptor Ligands

Parathyroid hormone receptors found on osteoblasts in bone and renal tubule cells in kidney elevate blood calcium levels when stimulated by parathyroid hormone (PTH) and PTH-related protein (PTHrP). Excessive secretion of PTH from the parathyroid gland results in primary hyperparathyroidism. Production of PTHrP by various tumors results in humoral hypercalcemia of malignancy. In both of these conditions, excessive blood calcium levels lead to clinically significant morbidity. A parathyroid hormone antagonist could therefore have therapeutic value.

Until now, no effective antagonists for the classical parathyroid hormone receptor (PTH1 receptor) were known. This invention describes a peptide which binds with high affinity (Kd = 1.3 +/- 0.1 nM, dissociation T1/2 = 14 min.) and acts as purely competitive antagonist at the PTH1 receptor. This novel peptide is related to tuberoinfundibular peptides of 39 residues (TIP39), also described in this invention, which binds to a related receptor. Deletion of amino acids from the N-terminus of TIP39 resulted in the high affinity PTH1 receptor antagonist peptide described here. This peptide may be used therapeutically to treat excessive blood calcium caused by PTH or PTHrP, other pathology caused by PTHrP, to demonstrate the utility of parathyroid hormone receptor antagonism in the treatment of hypercalcemia or other conditions, or to help screen for other antagonists at the parathyroid hormone receptor.