Oxytocin antagonists for assisted reproduction

Craciunas, Laurentiu; Tsampras, Nikolaos; Kollmann, Markus; Raine‐Fenning, Nick; Choudhary, Meenakshi

doi:10.1002/14651858.cd012375.pub2

Cited by 10 publications

(10 citation statements)

References 58 publications

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“…Molecular modeling showed that the preactivation energy (E preact ) for sulfur atom engagement by 4 Å in protected DDAVP depends on the iodinated amino acid: it is only ∼12 kcal/mol when iodine is on Mpa but becomes ∼18 kcal/mol when it is on Cys 6 . At the same time, protected terlipressin with a free amino group shows an identical preactivation energh of ∼22 kcal/mol, regardless of iodinated Cys 4 or Cys 9 , noticeably higher than that of DDAVP. To check if this difference comes from the influence of the N-terminal amino group, we calculated it for protected terlipressin with the tert-butoxycarbonyl (Boc)-protected amino group (Figure 2).…”

Section: ■ Results and Discussionmentioning

confidence: 95%

“…To check if this difference comes from the influence of the N-terminal amino group, we calculated it for protected terlipressin with the tert-butoxycarbonyl (Boc)-protected amino group (Figure 2). Strikingly, protection of the amino group drastically decreased the preactivation energy for Cys 9 -iodinated IM1, which became only 12 kcal/mol�very close to that of the more reactive DDAVP intermediate. Optimized calculated conformations of terlipressin and desmopressin are described in the Supporting Information (Figures S27 and S28).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Every year, FDA registers an increasing number of drugs belonging to this class. – Almost half of the existing peptide drugs are compounds with one or several S–S bridges. ,– The most well-known among them are analogues of the natural hormones somatostatin, oxytocin, and vasopressin: octreotide, atosiban, terlipressin, etc. , Over the past 7 years, 6 radiopharmaceuticals based on octreotide have been approved . Atosiban (“Tractocile”), desmopressin (DDAVP) (“Minirin”), and terlipressin (“Remestyp”, “Terlivaz”, and “Glypressin”) are now firmly established in clinical practice. – These drugs are structural analogues of oxytocin and Arg 8 /Lys 8 -vasopressin. Modifications of the native hormone structure, introduced in these peptides, are aimed at increasing their proteolytic stability and improving their pharmacokinetic characteristics. – …”

Section: Introductionmentioning

confidence: 99%

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Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group

Avdeev,

Ovchinnikov,

Medvedev

et al. 2023

Org. Process Res. Dev.

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An industry-ready approach for the synthesis of terlipressin is developed: the entire peptide chain assembly and subsequent disulfide bond closure are carried out on a polymeric carrier with a specific precaution for the protection of the Nterminal α-amino group. The effect of various factors on the purity of crude disulfide was studied, and the solid-phase cyclization process was optimized. The designed approach has high fidelity and reproducibility and is applicable for a large-scale peptide synthesis (we show it up to 15 g of the pure product). Using molecular modeling, we have found that the state of the N-terminal amino group (free or protected) has a significant influence on the ability of two cysteine side chains to reach each other, paving the way to a rational choice of protecting groups in peptide synthesis.

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Section: ■ Results and Discussionmentioning

confidence: 95%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group

Avdeev,

Ovchinnikov,

Medvedev

et al. 2023

Org. Process Res. Dev.

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“…Atosiban is a peptide analogous to the hypophyseal hormones AVP and OT and is used in Europe as a tocolytic agent for patients with imminent premature birth ( Craciunas et al, 2021 ). Species differences in the V1a and OTR sequences were not less pronounced.…”

Section: Discussionmentioning

confidence: 99%

Vasopressin V1a receptor and oxytocin receptor regulate murine sperm motility differently

et al. 2023

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Specific receptors for the neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin, are present in the male reproductive organs. However, their exact roles remain unknown. To elucidate the physiological functions of pituitary hormones in male reproduction, this study first focused on the distribution and function of one of the AVP receptors, V1a. In situ hybridization analysis revealed high expression of theAvpr1ain Leydig cells of the testes and narrow/clear cells in the epididymis, with the expression pattern differing from that of the oxytocin receptor (OTR). Notably, persistent motility and highly proportional hyperactivation were observed in spermatozoa from V1a receptor–deficient mice. In contrast, OTR blocking by antagonist atosiban decreased hyperactivation rate. Furthermore, AVP stimulation could alter the extracellular pH mediated by the V1a receptor. The results highlight the crucial role of neurohypophyseal hormones in male reproductive physiology, with potential contradicting roles of V1a and OTR in sperm maturation. Our findings suggest that V1a receptor antagonists are potential therapeutic drugs for male infertility.

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“…There was no signi cant difference in the incidence of adverse outcomes including miscarriage, multiple pregnancy, and ectopic pregnancy. Similarly, the Cochrane review published in 2021 [21] based on available data from RCTs has shown inconclusive conclusions about whether atosiban improves pregnancy outcomes in women receiving ART. Furthermore, according to Huang et al, [22] atosiban may be more appropriate for women undergoing RIF and has limited effect on the general female population undergoing IVF.…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of atosiban: a systematic review and a meta-analysis of randomized controlled trials and observational studies

Zhang

Feng

2022

Preprint

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Background: Atosiban has shown ameliorative effects in preterm birth (PTB), repeated implantation failure, and breech delivery by suppressing contractions, but its safety profile has not been fully established. Methods: Published randomized controlled trials and observational studies was electronically searched from inception to September 1, 2022. Our primary outcomes were maternal adverse events and neonatal comorbidities. Random effects model was used for data synthesis, and pooled risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated. Results: 43 studies comprising 11,772 patients were identified eligible. The incidence of maternal adverse events in atosiban group and controls were 4.0% and 12.4%, respectively. Overall, the risk of maternal adverse events and the discontinuation of treatment due to adverse events were significantly lower with atosiban compared with controls (RR 0.38, 95% CI [0.23, 0.61], P < 0.0001; RR 0.11, 95% CI [0.04, 0.29], P < 0.00001; respectively). The incidence of neonatal comorbidities was similar, and a higher risk of neonatal apnoea was observed in atosiban group compared with controls (RR 1.40, 95% CI [1.04, 1.90], P = 0.03). Conclusion: Atosiban has comparable efficacy and substantial better safety profile in the management of PTB, in vitro fertilization-embryo transfer (IVF-ET) and external cephalic version (ECV) compared with controls. Additionally, awareness of the presence of neonatal apnoea is required. In clinical practice, the appropriate treatment regimen needs to be selected according to the local circumstances and the individual patient condition.

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Oxytocin antagonists for assisted reproduction

Cited by 10 publications

References 58 publications

Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group

Formation of a Disulfide Bridge on the Resin during Solid-Phase Synthesis of Terlipressin: Influence of the Boc-Protected and Free N-Terminal Amino Group

Vasopressin V1a receptor and oxytocin receptor regulate murine sperm motility differently

Safety and efficacy of atosiban: a systematic review and a meta-analysis of randomized controlled trials and observational studies

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