Role of oxytocin in the initiation of term and preterm labor in rats: Changes in oxytocin receptor density and plasma oxytocin concentration and the effect of an oxytocin antagonist, L-366,509

Q1 · MEDICINE

Article

Author: Masuo Akahane ; Yukiyoshi Ajisawa ; Keiko Minami ; Tatsuhiko Kawarabayashi ; Yoshihito Inoue ; Mamoru Kobayashi ; Makoto Moro

OBJECTIVEOur purpose was to compare the functional roles of oxytocin in term and preterm labor in rats by both biochemical and pharmacologic means.STUDY DESIGNWe determined the myometrial oxytocin receptor density and the maternal plasma concentrations of oxytocin and progesterone on gestational days 18, 20, and 22 (morning) and at the onset of delivery (day 22 afternoon) in rats with labor at term and at the onset of delivery (day 20 afternoon) in rats in preterm labor induced by the combined use of bilateral ovariectomy and estradiol injection. We also evaluated the effects of an oxytocin antagonist, L-366,509, on the initiation of both term and preterm labor.RESULTSThe number of tritiated oxytocin binding sites in myometrial membranes rapidly increased on gestational day 22 (morning) in rats with term labor. Plasma progesterone level decreased in an inverse fashion. A rapid increase in circulating oxytocin concentration was observed at the onset of delivery in rats in labor at term. Both the plasma oxytocin concentration and the receptor density had the same values in rats with preterm labor as in rats with term labor. L-366,509 delayed the initiation of labor in rats with term and preterm labor in a dose-dependent manner.CONCLUSIONIt is confirmed biochemically and pharmacologically that oxytocin plays an important role in the initiation of both term and preterm labor in rats. The oxytocin antagonist examined was able to delay term and preterm labor, so it might prove useful in clinical practice for the treatment of preterm labor.

01 Mar 1994·Journal of Medicinal ChemistryQ1 · MEDICINE

1-(((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo[2.2.1]heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperazine (L-368,899): An Orally Bioavailable, Non-Peptide Oxytocin Antagonist with Potential Utility for Managing Preterm Labor

Q1 · MEDICINE

Article

Author: Williams, Peter D. ; Bock, Mark G. ; Carroll, LeighAnne ; Clineschmidt, Bradley V. ; Culberson, J. Chris ; Chiu, Shuet-Hing Lee ; Anderson, Paul S. ; Erb, Jill M. ; Ball, Richard G.

Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.

01 Dec 1993·Journal of Medicinal ChemistryQ1 · MEDICINE

Nanomolar-affinity, non-peptide oxytocin receptor antagonists

Q1 · MEDICINE

Article

Author: Bock, Mark G. ; Evans, Ben E. ; Lundell, George F. ; Rittle, Kenneth E. ; Gilbert, Kevin F. ; Leighton, James L. ; Carroll, Leigh Anne ; Pawluczyk, Joseph M. ; Williams, Peter D.

Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.

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Indication	Highest Phase	Country/Location	Organization	Date
Obstetric Labor, Premature	Discovery	US	Merck & Co., Inc.	10 Dec 1993

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