title: Improvement in potency of an oxytocin antagonist after systematic substitutions with L-tryptophan.
abstract: We report twelve analogues of [Pmp1,D-Trp2,Arg8]oxytocin, ANTAG (Pmp = beta, beta-pentamethylene-beta-mercaptopropionic acid), which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats, as measured in a uterotonic assay. Nine of the following analogues were designed by replacement of each of the nine residues in ANTAG with an L-tryptophan residue: [Ac-Trp1,D-Trp2,Val6,Arg8]OT, [Pmp1,Trp2,Arg8]OT, [Pmp1,D-Trp2,Trp3,Arg8]OT, [Pmp1,D-Trp2,Trp4,Arg8]OT, [Pmp1,D-Trp2,Trp5,Arg8]OT, [Aaa1,D-Trp2,Trp6,Arg8]OT, [Aaa1,D-Trp2,Val6,Arg8]OT, [Pmp1,D-Trp2,Ica7,Arg8]OT, [Pmp1,D-Trp2,Trp7,Arg8]OT, [Pmp1,D-Trp2,Trp8]OT, [Pmp1,D-Trp2,Arg8,Trp9]OT (11), [Pmp1,D-Trp2,Arg8,Trp(For)9]OT (12). In these analogues Aaa = 1-adamantaneacetic acid, and Ica = indoline-2-carboxylic acid. All linear analogues and analogues featuring Trp substitutions in the ring sequence of ANTAG were OT antagonists of lower potency than the parent peptide. All the analogues featuring Trp substitutions in the tail sequence of ANTAG were OT antagonists of equal or better potency than the parent peptide. Replacement with Ica7 gave analogue 8, equipotent with ANTAG, but replacement with Trp7 gave analogue 9, which shows almost a two-fold increase in potency (pA2 = 8.06). Replacement with Trp9 gave analogue 11 (pA2 = 8.03) which is about 1.8 times more potent than the parent antagonist, although Trp(For)9 had lower potency. Of great interest is that substitution with Trp8 leads to a more potent analogue, 10 (pA2 = 8.22), which, unlike most antidiuretic hormone antagonists, lacks any cationic charge in the molecule. The antidiuretic assay shows antagonists 9-11 to be weak antagonists of [Arg8]vasopressin, the antidiuretic hormone, with pA2 less than or equal to 6.0; hence, they may be interesting leads for future design of more potent and specific OT antagonists.
authors.affiliation: Department of Physiology, Northwestern University Medical School, Chicago, Illinois 60611.
authors.forename: G
authors.initials: G
authors.lastname: Flouret
authors.forename: W
authors.initials: W
authors.lastname: Brieher
authors.forename: T
authors.initials: T
authors.lastname: Majewski
authors.forename: K
authors.initials: K
authors.lastname: Mahan
authors.forename: L
authors.initials: L
authors.lastname: Wilson
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D010121:Oxytocin; D014364:Tryptophan