title: Effects of hydrophobic substitutions at position 18 on the potency of parathyroid hormone antagonists.
abstract: Position 18 in a parathyroid hormone (PTH) antagonist, [Nle8,18,Tyr34]bPTH(7-34)NH2 (ii), was shown to tolerate substitutions by a range of amino acids with retention of inhibitory activity. The effects of hydrophobic substitutions at this position as a means of enhancing binding interactions with the receptor were evaluated. Substitution of Nle at position 18 with either D-Ala, D-Trp, or L-Trp in analog ii or with Trp (D or L) in the recently reported, highly potent antagonist, [Nle8,18,D-Trp12,Tyr34]bPTH(7-34)NH2 (in vitro activities; Kb = 15 nM and Ki = 125 nM), was performed. In terms of activity on renal receptors, one antagonist, [Nle8,D-Trp12,18,Tyr34]bPTH(7-34)NH2, is the most active in vitro PTH antagonist yet reported (Kb = 4 nM; Ki = 30 nM). The rationale for design of this antagonist and the conclusions regarding PTH-receptor interactions are discussed.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
authors.forename: M
authors.initials: M
authors.lastname: Chorev
authors.forename: E
authors.initials: E
authors.lastname: Roubini
authors.forename: M E
authors.initials: ME
authors.lastname: Goldman
authors.forename: R L
authors.initials: RL
authors.lastname: McKee
authors.forename: S W
authors.initials: SW
authors.lastname: Gibbons
authors.forename: J E
authors.initials: JE
authors.lastname: Reagan
authors.forename: M P
authors.initials: MP
authors.lastname: Caulfield
authors.forename: M
authors.initials: M
authors.lastname: Rosenblatt
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000201:enzymology; D006801:Humans; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D018016:Receptors, Parathyroid Hormone