Oxytocin Antagonists: Clinical and Scientific Considerations

Thornton, Steven; Vatish, Manu; Slater, Donna M.

doi:10.1113/eph8602186

Cited by 34 publications

(21 citation statements)

References 31 publications

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“…The results of this study show that atosiban, a peptidic compound used in the management of preterm labor because of its antagonistic activity on uterine contractility (9,12,27), can also inhibit cell growth by acting as a selective agonist of OTR/G i coupling. This effect is indeed mediated by OTRs as it was only observed in MDCK and HEK293 cells stably transfected with human receptors but not in OTR-negative parental MDCK and HEK293 cells.…”

Section: Discussionmentioning

confidence: 96%

“…In myometrial and breast myoepithelial cells, OTR coupling to G q is responsible for phospholipase C (PLC) activation followed by inositol phosphate (InsP) and diacylglycerol production, increased intracellular calcium, and increased contractility (8). Accordingly, selective oxytocin analogues capable of blocking this pathway are employed in the treatment of preterm labor (9). The physiological role played by OTRs coupled to G i in myometrial cells is far less clear, although it was shown some years ago to also lead to an increase of cell contractility (10).…”

Section: S-labeled Guanosine 5-3-o-(thio) Trisphosphate ([ 35 S]gtp␥smentioning

confidence: 99%

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The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a “Biased Agonist” Mechanism

Reversi

Rimoldi

Marrocco

et al. 2005

Journal of Biological Chemistry

114

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In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G q and G i leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G i inhibits, whereas its coupling to G q stimulates, cell proliferation. WAF1/CIP1 induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a G i pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G q -phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.

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Section: Discussionmentioning

confidence: 96%

Section: S-labeled Guanosine 5-3-o-(thio) Trisphosphate ([ 35 S]gtp␥smentioning

confidence: 99%

The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a “Biased Agonist” Mechanism

Reversi

Rimoldi

Marrocco

et al. 2005

Journal of Biological Chemistry

114

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“…At present, the use of tocolytics to delay preterm labor is often contraindicated due to significant maternal and fetal side effects (14,15). A new FP receptor ligand, THG113, corresponding to a peptide derived from the sequence of the second extracellular loop of FP receptor (Fig.…”

mentioning

confidence: 99%

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Goupil

Tassy

Bourguet

et al. 2010

Journal of Biological Chemistry

113

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The prostaglandin F2␣ (PGF2␣) receptor (FP) is a key regulator of parturition and a target for pharmacological management of preterm labor. However, an incomplete understanding of signaling pathways regulating myometrial contraction hinders the development of improved therapeutics. Here we used a peptidomimetic inhibitor of parturition in mice, PDC113.824, whose structure was based on the NH 2 -terminal region of the second extracellular loop of FP receptor, to gain mechanistic insight underlying FP receptor-mediated cell responses in the context of parturition. We show that PDC113.824 not only delayed normal parturition in mice but also that it inhibited both PGF2␣-and lipopolysaccharide-induced preterm labor. PDC113.824 inhibited PGF2␣-mediated, G␣ 12 -dependent activation of the Rho/ROCK signaling pathways, actin remodeling, and contraction of human myometrial cells likely by acting as a non-competitive, allosteric modulator of PGF2␣ binding. In contrast to its negative allosteric modulating effects on Rho/ROCK signaling, PDC113.824 acted as a positive allosteric modulator on PGF2␣-mediated protein kinase C and ERK1/2 signaling. This bias in receptor-dependent signaling was explained by an increase in FP receptor coupling to G␣ q , at the expense of coupling to G␣ 12 . Our findings regarding the allosteric and biased nature of PDC113.824 offer new mechanistic insights into FP receptor signaling relevant to parturition and suggest novel therapeutic opportunities for the development of new tocolytic drugs.

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“…In contrast, if VP contributes to the regulation of uterine contractility, this is probably an endocrine effect. The role of OT and VP in the mechanisms of labour, both preterm and at term, is still not fully understood (Thornton et al 2001). It is unclear whether the onset of labour is caused by an increased amount of OT in circulating blood in both human and rat (Leake et al 1981, Higuchi et al 1985, Thornton et al 1992.…”

Section: Discussionmentioning

confidence: 99%

“…Although VP has been much less studied than OT in pregnancy, the foetus secretes VP during labour (Chard et al 1971) and the peptide may also be involved in stimulating uterine contractions. VP has been identified in the human myometrium during pregnancy (Thornton et al 2001), but local presence of VP mRNA has not been reported.…”

Section: Introductionmentioning

confidence: 96%

Expression of the oxytocin gene, but not the vasopressin gene, in the rat uterus during pregnancy: influence of oestradiol and progesterone

Bossmar¹,

Osman²,

Zilahi³

et al. 2007

Journal of Endocrinology

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Oxytocin (OT) and vasopressin (VP) are neurohypophyseal hormones with potent stimulatory actions on the uterus. In order to determine whether these hormones may have a paracrine action on the uterus, OT and VP gene expression was studied in myometrium from pregnant rats at gestational ages of 14 and 20 days, and from ovariectomized animals treated with oestradiol and progesterone. OT and VP mRNA concentrations were measured using real-time quantitative reverse transcription-PCR, and OT-and VP-like immunoreactivities were determined using RIA. OT mRNA was detected in the uterus from pregnant rats, but did not differ between the groups of different gestational ages. Oestradiol significantly (P!0 . 05) stimulated OT gene expression in ovariectomized rats. Progesterone alone was without effect on OT mRNA concentrations, but significantly (P!0 . 05) reduced the oestradiol-induced OT mRNA accumulation. The OT-like immunoreactivity in an extract of myometrium from pregnant rats was eluted from a reverse-phase HPLC column with a retention time identical to that of synthetic OT. Neither VP mRNA nor VP-like immunoreactivity was detected in the myometrium from pregnant or ovariectomized rats. The study demonstrates steroid-dependent expression of the OT gene in the rat uterus and processing of uterine preprooxytocin to the mature nonapeptide. The data support the theory that this peptide may act in a paracrine pathway. No evidence was found for the presence of VP in the uterus so that, if the hormone is involved in a stimulatory action on this tissue, it probably acts via an endocrine mechanism.

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Oxytocin Antagonists: Clinical and Scientific Considerations

Cited by 34 publications

References 31 publications

The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a “Biased Agonist” Mechanism

The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a “Biased Agonist” Mechanism

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Expression of the oxytocin gene, but not the vasopressin gene, in the rat uterus during pregnancy: influence of oestradiol and progesterone

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