title: Analogues of an in vitro parathyroid hormone inhibitor: modifications at the amino terminus.
abstract: Four analogues of parathyroid hormone were synthesized, based on a sequence previously shown to yield an in vitro inhibitor of PTH action. Binding properties of the analogues to presumed parathyroid hormone receptors were evaluated. Each of these analogues contains a structural alteration of the amino terminus of the compound [Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide. Each of the analogues--[desamino-Ser-3, Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide, [acetyl-Glu-4, Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide, [D-Ser-3, Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide, and [pyroGlu-4, Nle-8, Nle-18, Tyr-34]bPTH-3(3-34)amide--contains modifications selected to diminish or eliminate the weak PTH-like agonist properties detected in the parent compound in vivo. To permit valid comparison of receptor-binding properties, all the analogues were derived from a common solid-phase synthesis. When assayed in the renal adenylate cyclase assay, each of the compounds inhibited completely PTH-stimulated adenylate cyclase activity and was devoid of PTH-like agonist activity. To compare the binding affinity of the analogues for parathyroid hormone binding sites, the peptides were evaluated in a parathyroid hormone renal radioreceptor assay. Each peptide demonstrated a binding affinity comparable with one another and only slightly weaker than that of the unmodified inhibitory analogue, [Nle-8, Nle-18, Tyr-34]bPTH-(3-34)amide. These studies demonstrate that it is possible to alter the amino terminus of parathyroid hormone analogues without causing a dramatic decline in affinity for the parathyroid hormone receptor. Preservation of high receptor-binding affinity in these analogues indicates that synthesis of one or several of these peptides on a scale sufficiently large to permit in vivo evaluation of both agonist and antagonist properties is warranted.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D007672:Kidney Cortex / Q000378:metabolism; D007700:Kinetics; D010281:Parathyroid Hormone / Q000031:analogs & derivatives* / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018016:Receptors, Parathyroid Hormone; D013329:Structure-Activity Relationship
chemical_list: D010281:Parathyroid Hormone; D011956:Receptors, Cell Surface; D018016:Receptors, Parathyroid Hormone; D000262:Adenylyl Cyclases