Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the solid phase synthesis and some pharmacological properties of seven position two analogues (peptides 1-7) of one of our lead oxytocin antagonists, des-9-glycinamide[1-(beta-mercapto-beta,beta-pentamethylenepropionic+ ++ acid),2-O-methyltyrosine,4-threonine]ornithinevasotocin(desGly+ ++-NH2, d(CH2)5-[Tyr(Me)2,Thr4]OVT) (A). Peptides 1-7 have the following substituents at position two (1) D-Tyr(Me); (2) L-Tyr(Et); (3) D-Tyr(Et); (4) L-Tyr; (5) D-Tyr; (6) D-Phe and (7) D-Trp. These were evaluated for agonistic and antagonistic activities in in vitro and in vivo OT assays, in vivo vasopressor (V1a-receptor) assays and in vivo antidiuretic (V2-receptor) assays. None of the seven peptides exhibits oxytocic or vasopressor agonism. Peptides 1, 2, 4, 6 and 7 are extremely weak V2 agonists (V2 activities range from 0.001 to 0.02 U/mg). Peptides 3 and 5 exhibit weak V2 antagonism (pA2 < 6.0 and < 5.5, respectively). Peptides 1-7 exhibit potent in vitro (no Mg2+) OT antagonism (anti-OT pA2 values range from 7.66 to 8.03). Peptides 1 and 4-7 exhibit potent in vivo OT antagonism. Estimated in vivo anti-OT pA2 values range from 7.06 to 7.79 (peptides 2 and 3 were not tested). With anti-V1a pA2 values of 5.17-6.25 all seven peptides exhibit reduced anti-V1a potencies relative to the parent peptide (A) (anti-V1a pA2 = 6.46). Four of these peptides (4-7) exhibit striking gains in in vitro and in vivo anti-OT/anti-V1a selectivities compared to (A) which has an in vitro selectivity of 30 and an in vivo selectivity of 18. The D-Tyr2 (5), D-Trp2 (7), D-Phe2 (6) and L-Tyr2 (4) analogues of (A) exhibit anti-OT (in vitro)/anti-V1a selectivities = 240, 390, 404 and 540, respectively. The L-Tyr2 (4), D-Trp2 (7), D-Phe2 (6) and D-Tyr2 (5) analogues exhibited anti-OT (in vivo)/anti-V1a selectivities of 72, 80, 88 and 95, respectively. Peptides 4-7 appear to be the most selective peptide OT antagonists reported to date. In this regard it may be noted that they appear to be as or more potent and much more selective than the closely related OT antagonist 1-deamino[D-Tyr(Et)2,Thr4]OVT (Atosiban) which is currently undergoing clinical trial as a potential therapeutic agent for the prevention of premature labor. Atosiban (peptide 8) was resynthesized and pharmacologically evaluated in our laboratories. Atosiban exhibits the following antagonistic potencies. Anti-OT (in vitro, no Mg2+) pA2 = 7.71; anti-OT in vivo pA2 = 7.05; anti-V1a pA2 = 6.14 and anti-V2 pA2 approximately 5.9. Its anti-OT (in vivo)/anti-V1a selectivity is 8. Some of these antagonists may be suitable candidates for evaluation as potential tocolytic agents for use in the treatment of pre-term labor. They could also serve as useful new pharmacological tools for studies on the physiological roles of oxytocin. Finally, the findings presented here provide useful clues for the design of more potent and more selective OT antagonists.
 ...
PMID:Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban. 853 78

Sidaverin, a crystalline compound extracted from a polar fraction of Sida veronicaefolia (Lam), elicited oxytocin-like contractions in the non-gravid rat isolated uterus preparation with a concentration-response relationship. Equipotent concentrations of oxytocin and sidaverin, using matched responses, were approximately 0.16 U and 0.4 micrograms ml-1, respectively. Sidaverin-induced contractile response was atropine reversible. The concentration-response curves for sidaverin and oxytocin were parallel, and both responses were inhibited by the specific oxytocin antagonist, Atosiban, indicating possible involvement of oxytocin receptors in the action of sidaverin. There were potentiation of action of one drug to that of the other, irrespective of the order of administration and even after washing off the first before introducing the second drug. In the gravid uterus, sidaverin produced contractions in preparations from day 1 to day 6 or 7, caused relaxation in days 7-11, and elicited contractions in day 11 through term, the sensitivity of the preparations increasing exponentially toward term with strong sustained contractions. With the exception of days 7-11, when sidaverin antagonized oxytocin action, it potentiated action of oxytocin on the gravid uterus.
 ...
PMID:Interaction between oxytocin and 'sidaverin' on the gravid and non-gravid rat uterus. 866 53

The purpose of this study was to describe the course of preterm labor in patients receiving a standard intravenous infusion of the oxytocin antagonist atosiban. An open-labeled, non-randomized study was conducted at 4 sites. Successful tocolysis was defined as delay of delivery larger than 48 hours from starting atosiban and no need for an alternate tocolytic. Atosiban was administered by continuous intravenous infusion at a rate of 300 micrograms per minute until uterine contractions were absent for 6 hours, or up to a maximum infusion time of 12 hours. Sixty-two patients of between 20 and 36 weeks' gestation were enrolled over 6 months. One had rupture of membranes and was excluded. Successful tocolysis was noted in 43 of 61 (70.5%). Four delivered spontaneously within 48 hours and 14 (23.0%) required an alternate tocolytic agent. The chance of successful tocolysis was related to the degree of cervical dilation at the start of therapy. Cessation of uterine contractions was noted in 38 patients (62.3%). A decrease in uterine contraction frequency of 50% or more was noted in 50 of 61 patients (82.0%). Four patients reported side effects (nausea, vomiting, headache, dysguesia, chest pain), but in no case did side effects require discontinuation of the medication. Intravenous administration of atosiban is associated with a delay in delivery comparable to that seen with other tocolytics. If this effect is confirmed in planned placebo-controlled trials, its favorable side effect profile may give it a place in the armamentarium.
 ...
PMID:Treatment of preterm labor with the oxytocin antagonist atosiban. 868 3

Despite intensive efforts over three decades in many laboratories, attempts to design peptide antagonists of oxytocin (OT) which are more selective for OT uterine receptors than for vasopressin (AVP), vasopressor V1a receptors, have met with only limited success. We will review the current status of the field and report on studies in our laboratories which have led to the design of highly potent non-selective and selective OT antagonists. Virtually all are more potent (2-6 fold) and a number are more selective (10-12 fold) than Atosiban, currently in clinical trial as a tocolytic agent. Many of these new published and unpublished OT antagonists are thus promising candidates for development as potential tocolytic agents for the prevention of pre-term labor. We also report on promising new radioiodinatable ligands for OT receptors. All the new OT antagonists are valuable new tools for studies on the physiological roles of OT and as probes for OT and AVP receptors.
 ...
PMID:Advances in the design of selective antagonists, potential tocolytics, and radioiodinated ligands for oxytocin receptors. 871 21

We tested the hypothesis that increased oxytocin is a necessary mechanism for the mediation of androstenedione (delta 4A)-induced myometrial contractions by investigating the effects of maternal treatment with the oxytocin antagonist atosiban on in vivo delta 4A-induced contractions. In four monkeys (group I), maternal estradiol, oxytocin, and myometrial contractions were assessed at baseline and after continuous iv delta 4A administration. Similar measurements were made in three monkeys (group II) that received the same delta 4A infusion regimen, but in addition were treated daily with atosiban. Maternal estradiol and oxytocin levels and contractions were also assessed in four additional monkeys (controls; group III), in which the delta 4A vehicle, intralipid, was infused iv continuously. In group I, delta 4A induced myometrial contractions and increased maternal estradiol and oxytocin to term concentrations. No myometrial contractions occurred in group II monkeys after combined delta 4A and atosiban treatment despite estradiol being elevated to concentrations similar to those measured in group I monkeys. Atosiban had no effect on maternal heart rate or blood pressure. Maternal estradiol, oxytocin, and number of myometrial contractions remained unchanged from baseline values in control monkeys. In conclusion, oxytocin is a necessary part of the mechanisms mediating delta 4A-induced myometrial contractions. delta 4A promotes myometrial contractions via similar mechanisms that mediate spontaneous term contractions in pregnant monkeys.
 ...
PMID:The oxytocin antagonist atosiban prevents androstenedione-induced myometrial contractions in the chronically instrumented, pregnant rhesus monkey. 875 55

The oxytocin receptor antagonist [1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Om]-oxytocin (Atosiban) is a specific antagonist of both mesotocin- and oxytocin-induced myometrial contractions in late pregnant tammars in vitro. Continuous intravenous infusion of Atosiban (1 mg kg-1 day-1) for 3 or 7 days from day 24 of the 26.5 day gestation significantly delayed births. In both the 3 day and 7 day infusion groups, all 15 control animals were pregnant and gave birth within the normal time (day 26.75 +/- 0.20, mean +/- SEM), during the infusion of saline. The neonates weighed 387 +/- 8 mg. Deliveries were observed in 15 Atosiban-treated animals significantly (P < 0.05) later than in the controls (day 27.85 +/- 0.19; neonate weight 413 +/- 9 mg). All pouch young were successfully suckled, even in the continued presence of Atosiban. Baseline plasma concentrations of the prostaglandin F metabolite (PGFM) in pregnant tammars were < 200 pg ml-1. A surge in plasma PGFM occurred at birth (811 +/- 116 pg ml-1), followed by a rapid fall to baseline concentrations within 1 h after birth. This was observed both in saline- and in Atosiban-treated animals that gave birth during the observation period, and did not differ significantly between the treatment groups. Plasma progesterone concentrations in the control and the Atosiban-treated animals showed the normal pattern of luteolysis immediately after birth. Thus, infusion of an oxytocin receptor antagonist at the end of gestation delays birth, the peripartum surge in prostaglandin release, and the fall in progesterone, suggesting that mesotocin is an important part of the hormonal cascade associated with delivery in this marsupial.
 ...
PMID:Infusion with an oxytocin receptor antagonist delays parturition in a marsupial. 895 39

The oxytocin antagonist, atosiban (1-deamino-2-D-tyr(OET)-4-thr-8-orn-vasotocin/oxytocin), was infused i.v. to chronically instrumented pregnant baboons in the last third of pregnancy. Atosiban (6 microg/kg per min) inhibited myometrial electromyographic activity associated with spontaneous myometrial contractions that occurred around the onset of darkness between 134 and 162 days gestation (term 180 days gestation). The effect of atosiban on maternal heart rate was minimal. Maternal blood pressure remained unaltered during atosiban infusion. Fetal carotid arterial PO2 was unchanged during a 2-h infusion of atosiban. Transplacental passage of atosiban from mother to fetus was assessed at cesarean section under halothane anesthesia in four baboons and in two chronically instrumented fetuses in the absence of anesthesia. The maternal:fetal concentration gradient ranged from 9.2 to 22.8. Maternal atosiban clearance rates were 9.2-16.9 ml/kg per min. In conclusion, atosiban was very effective at inhibiting spontaneously occurring nocturnal myometrial contractions during the last third of gestation in the pregnant baboon. Although atosiban crosses the placenta relatively freely, there was no effect on fetal oxygenation.
 ...
PMID:Effect of the oxytocin antagonist atosiban (1-deamino-2-D-tyr(OET)-4-thr-8-orn-vasotocin/oxytocin) on nocturanl myometrial contractions, maternal cardiovascular function, transplacental passage, and fetal oxygenation in the pregnant baboon during the last third of gestation. 924 Oct 45

Inhibition of milk ejection in cows by oxytocin receptor blockade (Atosiban) and alpha-adrenergic receptor stimulation (phenylephrine) prior to prestimulation was compared with inhibition of milk ejection in unfamiliar surroundings. In addition, Atosiban and phenylephrine were administered after a 1 min prestimulation or 1 min after the start of milking. Oxytocin concentrations increased during milking in all treatments. The spontaneously removed milk fraction (before oxytocin was injected) was similar for Atosiban and phenylephrine treatments and in unfamiliar surroundings, but lower than in controls. Peak flow rates were similar in all treatments, but reduced as compared with controls when phenylephrine and Atosiban were administered before prestimulation. Peripheral (Atosiban, phenylephrine) and central (unfamiliar surroundings) inhibition of milk ejection reduced the amount of available milk similarity. Drug treatments resulted in similar peak flow rates; however, teats were contracted after phenylephrine administration but not after Atosiban. The inhibition induced by Atosiban could be abolished by oxytocin injection, but not induced by phenylephrine, which was antagonized by alpha-adrenergic receptor blockade. These results indicate that inhibition of milk ejection through activation of alpha-adrenergic receptors is based on blockade of milk flow into the cistern, but not through the teats.
 ...
PMID:Inhibition of milk ejection in cows by oxytocin receptor blockade, alpha-adrenergic receptor stimulation and in unfamiliar surroundings. 927 52

1. The exact nature of the receptor subtype(s) involved in the action of arg-vasopressin (AVP) on the rat aorta and small mesenteric artery (SMA) is controversial. Therefore, we have studied the effects of the selective V1A receptor antagonists, OPC 21268 and SR 49059, and the oxytocin (OT) receptor antagonist, atosiban, on the AVP- and OT-induced contractions of the two vessels. 2. AVP and OT displayed similar intrinsic activities in the rat aorta and SMA, but AVP was approximately 130 fold and approximately 500 fold more potent than OT, respectively. In the rat aorta, Hill slopes (nH) were similar for OT and AVP. However, in rat SMA, the OT concentration-effect (E/[A]) curve was significantly steeper than the AVP E/[A] curve (nH, = 3.3+/-0.20, 2.3+/-0.15; P<0.001). 3. In the aorta OPC 21268, SR 49059 and atosiban competitively antagonized the AVP and OT E/[A] curves. Except for atosiban and SR 49059 against AVP, competitive antagonism was also observed in the SMA. Atosiban caused concentration-dependent steepening of the AVP E/[A] curve, whereas SR 49059 decreased the upper asymptote. 4. Schild analysis yielded affinities indicative of V1A receptor involvement in both vessels: pKB/ pA2=9.20 9.48, 7.56 7.71 and 6.19 6.48 for SR 49059, OPC 21268 and atosiban, respectively. 5. Neither AVP nor OT relaxed U46619 pre-contracted aorta or SMA in the presence of SR 49059, suggesting no interference of a vasodilatory component. 6. Despite predominant involvement of V1A receptors in both vessels, the different Hill slopes of AVP and OT E/[A] curves as well as the steepening of the AVP E/[A] curves by atosiban are indicative of receptor heterogeneity in the rat SMA.
 ...
PMID:Characterization of receptors mediating contraction of the rat isolated small mesenteric artery and aorta to arginine vasopressin and oxytocin. 983 26

Genital inflammation may play a major role in the pathogenesis of preterm labor. Screening and early treatment of subclinical genital tract infections (bacterial vaginosis, heavy group B streptococci colonization, primary genital HSV infection and other silent intra-uterine infections) seem to offer promise for the prevention of preterm labor. New factors have been studied in order to appreciate their benefit in the evaluation of the risk of preterm labor. None of these biologic markers (fetal-fibronectin, maternal interleukin-6, vaginal pH measuring) have enough sensitivity to permit efficient screening. Home uterine activity monitoring seems to be interesting for early identification of women with increased risk of preterm delivery, but can't be used on a large scale because of its costs. New tocolytic agents are investigated in order to protect from an adverse outcome. Atosiban exhibits more oxytocin selective and antagonistic activity without side-effects, and nimesulide seems to have a lack of effects on fetal functions.
 ...
PMID:[The threat of premature labor: new aspects for management]. 986 33


1 2 3 4 5 Next >>