Design of potent oxytocin antagonists featuring D-tryptophan at position 2

Flouret, George; Brieher, William M.; Mahan, Kevin; Wilson, Laird

doi:10.1021/jm00106a027

Cited by 29 publications

(32 citation statements)

References 4 publications

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“…A baboon model was chosen for this study because it forms a single discoid placenta which is similar to the human and different to that of the rhesus monkey, which normally has a bilobed placenta [ 11 ]. A laparotomy was necessary for anchoring the cannulae to the uterine serosa and to tunnel them for protec tion.…”

Section: Discussionmentioning

confidence: 99%

A Non-Human Primate Model for the in utero Chronic Catheterization of the Umbilical Vein

Lémery

Santolaya-Forgas²,

Wilson³

et al. 1995

Fetal Diagn Ther

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Short-term ultrasound-guided fetal umbilical cord catheterization in humans has been reported. However, before chronic umbilical vein catheterization is attempted in humans the technique must be tested in the non-human primate model. If the fetus was to tolerate this procedure, chronic fetal umbilical vein catheterization could be used for drug administration, parenteral fetal nutrition or to monitor the changes of hematologic parameters during and after open or endoscopic fetal surgery. In this study, 4 pregnant baboons were used to test the feasibility of ultrasound-guided umbilical vein catheterization. Although the umbilical vein was successfully catheterized in all the animals, only 1 fetus survived the postoperative period. The 3 immediate fetal deaths were due to a fetal intra amniotic hemorrhage, while the most likely cause of death of the 4th animal was infection. In the surviving fetus and mother, blood was sampled once a day. Neither fetomaternal hemorrhage nor thrombosis could be documented. We conclude that ultrasound-guided transplacental umbilical vein chronic catheterization is technically difficult but feasible in the baboon model. Further studies in this model are needed to improve the catheterization technique and to monitor the extent of time that the catheter may be tolerated within the umbilical vein.

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Section: Discussionmentioning

confidence: 99%

A Non-Human Primate Model for the in utero Chronic Catheterization of the Umbilical Vein

Lémery

Santolaya-Forgas²,

Wilson³

et al. 1995

Fetal Diagn Ther

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“…Over the years a number of OTAs have been synthesized, including oxytocin-derived peptidyl [11][12][13][14][15][16][17], non-oxytocin-derived peptidyl [18], and non-oxytocin-derived non-peptidyl compounds [19,20]. Only recently have laboratories focused on developing OTAs for inhibiting preterm labor in humans.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent review of the literature, Higby and co-workers [1] concluded that among those tocolytic agents commonly used (i.e., 3-sympathomimetics, MgSO 4 , calcium channel blockers, and indomethacin), only prostaglandin synthesis inhibitors are effective in the treatment of preterm labor. The development of OTAs, both peptidyl [11][12][13][14][15][16][17][18] and non-peptidyl [19,20], as potential tocolytic agents for humans in preterm labor has recently been reported, and clinical evaluation is being performed on several of them [21]. The ideal therapeutic agent for the treatment of preterm labor should be highly specific and have minimal side effects.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Binding Affinity of Oxytocin Antagonists to Human and Rat Uterine Oxytocin Receptors and their Correlation to the Rat Uterine Oxytocic Bioassay1

Pak

Bertoncini

Meyer

et al. 1994

Biology of Reproduction

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One of the primary methods used to screen the development of oxytocin antagonists (OTAs) is the rat oxytocic bioassay. The purpose of this study was to determine whether the rat oxytocic bioassay is a good predictor of binding affinity to human and rat uterine oxytocin receptors (OTr). The binding affinities of five OTAs to human and rat uterine OTr were determined and correlated with pA2 values derived from the rat uterine oxytocic bioassay. Human uterine myometrial tissue was obtained from patients at the time of cesarean section. Rat uterine tissue for the OTr assay was taken at Day 21 of pregnancy. OTr assays were accomplished by isolating uterine cell membranes and performing saturation analysis with cold OTAs and tritium-labeled oxytocin. The association constants (Ka; 10(+8)/M) were calculated by nonlinear curve-fitting techniques. The Ka for the five OTAs (Mpa1-OT, Antag I, L366948, Antag II, and Antag III), as estimated from the human OTr assay, were 0.55, 0.60, 2.27, 1.91, and 47.20, respectively. Ka estimates obtained through use of rat uterine membranes were 0.51, 1.16, 5.89, 2.03, and 24.40, respectively. Correlation of the log10 of the rat oxytocic bioassay results with those of the rat and human OTr assay was 0.94 and 0.98, respectively (p < 0.01). Antag III was approximately 55, 48, and 90 times more potent than Mpa1-OT as determined by the rat bioassay and rat and human uterine OTr assays, respectively. Mpa1-OT is an OTA that is currently undergoing clinical evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Stepwise improvement of OT-R binding affinity, and antagonist potency, as well as OT/AVP receptor selectivity [238,239,240], led to a final compound, 18, termed Antag III, or TT-235 [241] [see Fig. (7)], which is reported to have 90-fold higher affinity for the OT-R than atosiban [242], and to be 50-fold more efficacious in a baboon model of uterine contractions [243].…”

Section: Peptide Antagonistsmentioning

confidence: 99%

Preterm Labour: An Overview of Current and Emerging Therapeutics

Schwarz¹,

Page²

2003

CMC

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Preterm labour is a major cause of perinatal mortality and morbidity. However, during the past 40 years of clinical studies and despite the use of multiple therapeutic agents, the rate of preterm birth has not drastically declined. In 1991, it was estimated that in the US approximately 116,000 women admitted with acute episodes of preterm labour were treated each year with ritodrine, which is the first drug approved by the US FDA and still remains the standard therapy for treating preterm labour. Ritodrine (Yutopar( trade mark )) stimulates the beta(2)-adrenergic receptor throughout the body, causing an inhibitory action in different tissues that, among other side effects, also leads to an attenuation of uterine contractility. More recently, a new therapeutic agent, atosiban (Tractocile( trade mark )), a peptidic oxytocin receptor antagonist, has been introduced to the market. However, the use of the various pharmacological agents to treat preterm labour remains restricted, due to lack of uterine selectivity, low efficacy and potentially serious side effects for the mother or the foetus. Therefore, there is an urgent need to develop drugs with myometrial selectivity that would allow long-lasting inhibition of labour and prolong pregnancy up to a stage when good foetal maturation raises the chances of survival. One of the major obstacles hampering the development of new therapeutic agents is the marked inter-species difference in terms of preterm labour physiology, which complicates the preclinical evaluation of new candidate molecules in animal models of disease. In this review, the authors will provide a comprehensive update of past, current and new approaches for the management of preterm labour, including beta(2)-adrenergic agonists, calcium channel blockers, oxytocin antagonists, prostaglandin antagonists and other potential therapeutics. For each of the therapies used today, the review will cover the mechanism of action, benefit and adverse effects, and discuss the promise and potential benefits of new emerging therapeutic agents.

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Design of potent oxytocin antagonists featuring D-tryptophan at position 2

Cited by 29 publications

References 4 publications

A Non-Human Primate Model for the in utero Chronic Catheterization of the Umbilical Vein

A Non-Human Primate Model for the in utero Chronic Catheterization of the Umbilical Vein

Comparison of Binding Affinity of Oxytocin Antagonists to Human and Rat Uterine Oxytocin Receptors and their Correlation to the Rat Uterine Oxytocic Bioassay1

Preterm Labour: An Overview of Current and Emerging Therapeutics

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