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Endocrinology, Vol 123, 2597-2599, Copyright © 1988 by Endocrine Society
ARTICLES |
ME Goldman, RL McKee, MP Caulfield, JE Reagan, JJ Levy, CT Gay, PA DeHaven, M Rosenblatt and M Chorev
Department of Biological Research and Molecular Biology, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
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.
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