title: In vitro pharmacological profile of a novel structural class of oxytocin antagonists.
abstract: A number of structurally novel cyclic hexapeptides have been characterized as potent and selective oxytocin (OT) antagonists in vitro. As a representative of this class of compounds, L-366,948 [[cyclo(L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl- L-pipecolyl-D- histidyl)]] exhibited a high binding affinity (Ki, low nanomolar) for OT receptors in rat (uterus and mammary) and primate (pregnant rhesus and human myometrium) tissue with a several hundred-fold binding selectivity vs. rat arginine vasopressin (AVP)-V1 (liver) and AVP-V2 (kidney medulla) receptors. In functional assays, L-366,948 was a pure OT antagonist, blocking both OT-stimulated contraction of the isolated rat uterus (pA2, 8.5) and phosphatidylinositol turnover in uterine slices (IC50, 40 vs. 3 nM OT), with no evidence of partial agonist activity. L-366,948 was comparatively weak as an antagonist of AVP-induced contraction of the isolated rat tail artery (AVP-V1 receptor) and AVP-stimulated adenylate cyclase (AVP-V2 receptor) activity in rat kidney medulla and did not influence prostaglandin F2 alpha- or bradykinin-induced contractions of the isolated rat uterus. L-366,948 and related compounds described in this report represent new experimental tools for the study of the pharmacology and physiology of OT.
authors.affiliation: Department of New Lead Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
authors.forename: D J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: B V
authors.initials: BV
authors.lastname: Clineschmidt
authors.forename: E V
authors.initials: EV
authors.lastname: Lis
authors.forename: D R
authors.initials: DR
authors.lastname: Reiss
authors.forename: J A
authors.initials: JA
authors.lastname: Totaro
authors.forename: C J
authors.initials: CJ
authors.lastname: Woyden
authors.forename: M G
authors.initials: MG
authors.lastname: Bock
authors.forename: R M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: R D
authors.initials: RD
authors.lastname: Tung
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors; D005260:Female; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: D010456:Peptides, Cyclic; D014316:Tritium; D001127:Arginine Vasopressin; C060102:L 365209; C066874:L 366682; C066873:L 366948; D010121:Oxytocin