A new highly potent parathyroid hormone antagonist: [D-Trp12,Tyr34]bPTH-(7-34)NH2

• Published in: Endocrinology (Philadelphia) Vol. 123; no. 5; p. 2597
• Main Authors: Goldman, M E, McKee, R L, Caulfield, M P, Reagan, J E, Levy, J J, Gay, C T, DeHaven, P A, Rosenblatt, M, Chorev, M
• Format: Journal Article
• Language: English
• Published: United States 01.11.1988
• Subjects: Adenylyl Cyclases - metabolism; Adenylyl Cyclases - pharmacology; Animals; Binding, Competitive; Bone and Bones - metabolism; Cattle; Cell Membrane - metabolism; Kidney - metabolism; Parathyroid Hormone - antagonists & inhibitors; Parathyroid Hormone - metabolism; Parathyroid Hormone - pharmacology; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Receptors, Cell Surface - metabolism; Receptors, Parathyroid Hormone; Structure-Activity Relationship
• ISSN: 0013-7227
• DOI: 10.1210/endo-123-5-2597

Based upon N-terminal parathyroid hormone (PTH) analog structure-activity relationship studies, position 12 was found to possess a wide structural latitude and was chosen as a site for single amino acid substitutions. Replacement of the naturally-occurring Gly with D-Trp at position 12 in the PTH antagonists [Tyr34]bPTH-(7-34)NH2 and [Nle8,18,Tyr34]bPTH-(7-34)NH2 increased in vitro receptor affinity. The D-Trp12 containing analogs were 12-fold more potent than their unsubstituted counterparts as inhibitors of PTH binding to renal and bone PTH receptors and 13-27-fold more potent as inhibitors of PTH-stimulated renal and bone adenylate cyclase activity. Based upon Scatchard analyses of saturation binding experiments and Schild analyses of adenylate cyclase experiments, [D-Trp12,Tyr34]bPTH-(7-34)NH2 was shown to interact with PTH receptors in a competitive manner. These studies demonstrate, therefore, that D-Trp12 substitution in PTH antagonists improves inhibitory properties in vitro and is compatible with a helical conformation at this position as a new direction for the design of PTH antagonists.