WR-2721 inhibits parathyroid adenylate cyclase.

Abstract

WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is a chemoprotective and radioprotective agent that has been shown to lower serum calcium in dogs and in humans. This is secondary both to impaired release of Ca2+ from bone and diminished secretion of parathyroid hormone (PTH) from parathyroid glands. Because cAMP plays a role in the regulation of PTH secretion and WR-2721 has been shown to lower cAMP levels in radiated mouse spleen, we investigated the effects of WR-2721 on cAMP production in dispersed bovine parathyroid cells. Additionally, we studied the adenylate cyclase in plasma membranes from normal bovine parathyroid glands after exposure to WR-2721. With parathyroid cells incubated at 0.5 mM Ca2+, addition of WR-2721 in concentrations ranging from 0.02 to 2.0 mM resulted in a progressive decrease in intracellular cAMP (42-50%, respectively). In plasma membranes of bovine parathyroid cells a dose-dependent decrease in adenylate cyclase activity was noted. Inhibition of the cyclase was seen over a wide range of Mg2+ concentrations (2.5-40 mM). WR-2721 inhibited both basal and NaF, Gpp(NH)p, forskolin, and pertussin toxin-stimulated adenylate cyclase. These data suggest that WR-2721 inhibits the activity of parathyroid adenylate cyclase.