Mono- and bicyclic analogs of parathyroid hormone-related protein. 1. Synthesis and biological studies

The bioactive conformation of parathyroid hormone-related protein (PTHrP), a single-chain linear peptide structurally similar to parathyroid hormone (PTH), is of considerable interest because PTH and PTHrP both recognize and bind to a shared G-protein-coupled receptor. Both hormones are thought to present a bioactive conformation to the receptor which is substantially α-helical in nature. To better characterize this putative biologically relevant conformation, we prepared a series of conformationally constrained analogs of PTHrP with enhanced α-helical stability. A combination of structural constraint and helix stabilization was achieved through side chain-to-side chain lactam ring formation between Lysi and Aspi+4 residues (13-to-17 and 26-to-30) along the PTHrP sequence. Mono- and bicyclic analogs derived from the agonist PTHrP-(1−34)NH2 and the antagonist PTHrP-(7−34)NH2 were prepared and characterized in terms of receptor binding and stimulation (or antagonism) of PTH-stimulated adenylyl cyclase activ...