Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

Manning, Maurice; Cheng, Ling; Stoev, S.; Wo, Nga Ching; Çhan, W. Y.; Szeto, Hazel H.; Durroux, Thierry; Mouillac, Bernard; Barberis, Claude

doi:10.1002/psc.667

Cited by 26 publications

(18 citation statements)

References 108 publications

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“…It was equipotent at rat OT and V2 receptors and 10-fold selective for rat OT vs. rat V1 receptors ( Table 1). The selectivity of atosiban was very similar to that reported in the literature by various groups (6,20,36). For example, Cirillo et al (6) found that atosiban was 23-fold more potent at hV1a than hOT and only 8 and 12-fold more potent at hOT than V1b and V2, respectively.…”

Section: Resultssupporting

confidence: 69%

“…Peptide antagonists that are more potent and selective than atosiban have been identified. For example, those described by both Manning et al (20) and Stymiest et al (32) are reported to be as potent as GSK221149A. However, the most selective peptide described by Manning et al (20) is only 6.5-fold selective for human OT vs. human V1a receptors, and no selectivity data are reported by Stymiest et al (32).…”

Section: Discussionmentioning

confidence: 82%

“…It has been shown to reduce uterine contractions in vitro and in vivo and arrest preterm labor in pregnant women, resulting in a delay of delivery (13). While atosiban is efficacious at delaying delivery for 48 h, its use to prolong pregnancy beyond 48 h has been limited because it is only available for parenteral administration.Significant progress has been made in identifying both peptide and nonpeptide oxytocin receptor antagonists (1,6,20,25, 27,31,32,37). However, even though the newly developed peptide antagonists [such as barusiban and those described by Manning et al (20) and Stymiest et al (32)] are more potent and selective and serve as good research tools, their use in the clinic is still limited by having to be administered parenterally.…”

mentioning

confidence: 96%

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Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

McCafferty¹,

Pullen²,

Wu³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3R,6R)-3-Indan-2-yl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity (K(i) = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (K(i) = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA(2) value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID(50) = 0.27 +/- 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19-21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.

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Section: Resultssupporting

confidence: 69%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 96%

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Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

McCafferty¹,

Pullen²,

Wu³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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show abstract

“…In vivo bioassays show that these two antagonists show selectivity for action at the oxytocin receptor over the vasopressin V 1a receptor (36). At the same time that the jugular cannulation was performed, an osmotic minipump (model 1007D, Durect Corp., Cupertino, CA) was implanted.…”

Section: Study 3: Effect Of Oxytocin Receptor Antagonistsmentioning

confidence: 99%

Gonadal Steroid Modulation of Stress-Induced Hypothalamo-Pituitary-Adrenal Activity and Anxiety Behavior: Role of Central Oxytocin

et al. 2006

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Intracerebroventricular administration of oxytocin reduces anxiety behavior and hypothalamo-pituitary-adrenal (HPA) responses to stress in female rats. Similar changes are seen in late-pregnant rats, and oxytocin-sensitive pathways may mediate these effects. This study investigated anxiety behavior and stress responses using a gonadal steroid model of late pregnancy, which is known to increase endogenous oxytocin expression. Compared with continuous progesterone treatment, 3-d withdrawal of progesterone after 11-d treatment of ovariectomized rats with estradiol and progesterone resulted in increased binding of the oxytocin receptor ligand [(125)I]d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]ornithine vasotocin in selective forebrain regions, including the ventrolateral septum and ventromedial hypothalamus. Behavior in the elevated plus-maze indicated that progesterone withdrawal had an anxiolytic effect, and this was associated with lower levels of c-fos mRNA expression in the ventral hippocampus, an area previously shown to be sensitive to oxytocin. In other groups of animals, the plasma corticosterone response to a psychological stress (10 min of 114 dB white noise) was significantly attenuated by this steroid manipulation. Furthermore, simultaneous infusion of the selective oxytocin receptor antagonist desGlyNH(2), d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT during the period of progesterone withdrawal reversed this attenuation of noise-induced HPA activation, indicating a role for endogenous oxytocin in this effect. Thus, mimicking the steroid profile of late pregnancy leads to a reduction in anxiety behavior and attenuates HPA activity induced by mild stress. These effects appear to be mediated through the involvement of central oxytocin neurotransmission.

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“…Typical experimental data are presented in Fig. 6a and are fitted (Manning et al, 2001(Manning et al, , 2005 (Fig. 6b).…”

Section: Cooperative Binding Probes Gpcr Dimer Existence 1785mentioning

confidence: 99%

Probing the Existence of G Protein-Coupled Receptor Dimers by Positive and Negative Ligand-Dependent Cooperative Binding

Albizu

Balestre²,

Breton³

et al. 2006

Mol Pharmacol

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An increasing amount of ligand binding data on G proteincoupled receptors (GPCRs) is not compatible with the prediction of the simple mass action law. This may be related to the propensity of most GPCRs, if not all, to oligomerize. Indeed, one of the consequences of receptor oligomerization could be a possible cross-talk between the protomers, which in turn could lead to negative or positive cooperative ligand binding. We prove here that this can be demonstrated experimentally. Saturation, dissociation, and competition binding experiments were performed on vasopressin and oxytocin receptors expressed in Chinese hamster ovary or COS-7 cells. Linear, concave, and convex Scatchard plots were then obtained, depending on the ligand used. Moreover, some competition curves exhibited an increase of the radiotracer binding for low concentrations of competitors, suggesting a cooperative binding process. These data demonstrate that various vasopressin analogs display either positive or negative cooperative binding. Because positive cooperative binding cannot be explained without considering receptor as multivalent, these binding data support the concept of GPCR dimerization process. The results, which are in good accordance with the predictions of previous mathematical models, suggest that binding experiments can be used to probe the existence of receptor dimers.

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Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

Cited by 26 publications

References 108 publications

Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

Gonadal Steroid Modulation of Stress-Induced Hypothalamo-Pituitary-Adrenal Activity and Anxiety Behavior: Role of Central Oxytocin

Probing the Existence of G Protein-Coupled Receptor Dimers by Positive and Negative Ligand-Dependent Cooperative Binding

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