Oxytocin Analogues Research Articles

Development and characterisation of novel, enzymatically stable oxytocin analogues with beneficial antidiabetic effects in high fat fed mice

BackgroundThere is growing evidence to support beneficial effects of the hypothalamic synthesised hormone, oxytocin, on metabolism. However, the biological half-life of oxytocin is short and receptor activation profile unspecific. MethodsWe have characterised peptide-based oxytocin analogues with structural modifications aimed at improving half-life and receptor specificity. Following extensive in vitro and in vivo characterisation, antidiabetic efficacy of lead peptides was examined in high fat fed (HFF) mice. ResultsFollowing assessment of stability against enzymatic degradation, insulin secretory activity, receptor activation profile and in vivo bioactivity, analogues 2 N (Ac-C ˂YIQNC >PLG-NH2) and D7R ((d-C)YIQNCYLG-NH2) were selected as lead peptides. Twice daily injection of either peptide for 22 days reduced body weight, energy intake, plasma glucose and insulin and pancreatic glucagon content in HFF mice. In addition, both peptides reduced total- and LDL-cholesterol, with concomitant elevations of HDL-cholesterol, and D7R also decreased triglyceride levels. The two oxytocin analogues improved glucose tolerance and insulin responses to intraperitoneal, and particularly oral, glucose challenge on day 22. Both oxytocin analogues enhanced insulin sensitivity, reduced HOMA-IR and increased bone mineral density. In terms of pancreatic islet histology, D7R reversed high fat feeding induced elevations of islet and beta cell areas, which was associated with reductions in beta cell apoptosis. Islet insulin secretory responsiveness was improved by 2 N, and especially D7R, treatment. ConclusionNovel, enzymatically stable oxytocin analogues exert beneficial antidiabetic effects in HFF mice. General significanceThese observations emphasise the, yet untapped, therapeutic potential of long-acting oxytocin-based agents for obesity and type 2 diabetes.

COMPARATIVE STUDY BETWEEN OXYTOCIN AND PROSTAGLANDIN IN INDUCTION OF DELIVERY IN POST TERM PREGNANCY

Induction of delivery using medication can be performed by stimulating uterine contractility for establishing delivery prior to the start of spontaneous labor. Two most common ecbolic are Oxytocin and prostaglandins analogues (PGs) e.g. misoprostol. The study aims to compare between the effects of oxytocin & misoprostol in ripening of the cervix and induction of delivery in postdate pregnancy. Results show that the induction delivery period mean was significantly higher when using misoprostol than when using oxytocin. No significantly different results between the both groups regarding uterine hyperstimulation. No significantly different results between the both groups regarding postpartum hemorrhage. No significantly different results between the both groups regarding the mode of delivery. No significantly different results between the both groups regarding Cesarean section indication. No significantly different results between the both groups regarding the mean of Apgar score at 1 and 5 minutes. No significantly different results between the both groups regarding meconium aspiration. No significantly different results between the both groups regarding emergency Cesarean section rate due to fetal distress (pathological fetal heart rates) between the two groups. There was no significant difference between the two groups as regards the neonatal admission to the intensive care unit (N.I.C.U). It is concluded that Usage of both IV oxytocin 5 mIU/minute & vaginal misoprostol 25 µg is safe to induce delivery. It is preferable to use IV oxytocin 5 mIU/minute if the time factor is considered.
 Keywords: oxytocin, prostaglandin, induction of delivery, postdate pregnancy

On-Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool.

The ability to modify peptides and proteins chemoselectively is of continued interest in medicinal chemistry, with peptide conjugation, lipidation, stapling, and disulfide engineering at the forefront of modern peptide chemistry. Herein we report a robust method for the on-resin preparation of allenamide-modified peptides, an unexplored functionality for peptides that provides a versatile chemical tool for chemoselective inter- or intramolecular bridging reactions with thiols. The bridging reaction is biocompatible, occurring spontaneously at pH 7.4 in catalyst-free aqueous media. By this "click" approach, a model peptide was successfully modified with a diverse range of alkyl and aryl thiols. Furthermore, this technique was demonstrated as a valuable tool to induce spontaneous intramolecular cyclisation by preparation of an oxytocin analogue, in which the native disulfide bridge was replaced with a vinyl sulfide moiety formed by thia-Michael addition of a cysteine thiol to the allenamide handle.

Carbetocin Or Oxytocin To Prevent Postpartum Haemorrhage Due To Uterine Aony In Cases Of Elective Caesarean Section


 
 
 Background: Despite the technological advancement made in the past few decades, postpartum haemorrhage (PPH) remains one of the principal causes of maternal deaths in developing nations. The administration of uterotonic drugs widely prevents the PPH; therefore, it is the main point of active management. Among uterotonics, oxytocin has proven to be very effective in reducing the incidence of PPH. One prophylactic drug which has been introduced in recent times is carbetocin, a synthetic long-acting oxytocin analogue. It has a longer half life of 41 min, allowing it to stimulate a prolonged uterine response of up to an hour after a single intravenous dose, obviating the need for infusion.
 Methods: A total of 120 pregnant women divided into two groups; Group I (Carbetocin group) included 60 women who received carbetocin and delivered by caesarean section (CS), Group II (Oxytocin group) included 60 women who received oxytocin and delivered by caesarean section (CS).
 Results: Our result showed that, there was a statistically significant difference for the prevention of atonic postpartum hemorrhage between the two groups (p<0.01), for carbetocin group. There was also a statistically significant difference between the two groups (p < 0.01), according to need to additional procedures, such as need to modified B-lynch sutures and need to bilateral uterine arteries ligation for carbetocin group.
 
 
 
 Conclusion: We concluded that carbetocin was a better alternative to traditional oxytocin in the prevention of PPH after elective caesarean section.
 
 
 
 
 

Efficacy and Safety of Carbetocin for the Prevention of Primary PPH During Caesarean Section: An Open Label Single Arm Study

Background: The risk of postpartum haemorrhage is much higher for women undergoingcaesarean section, particularly in developing countries where the majority of operations arecarried out as an emergency procedure. Postpartum haemorrhage is the leading cause ofmaternal mortality worldwide. Around 67–80% of cases are caused by uterine atony.Preventive measures include prophylactic drugs use to aid uterine contraction after delivery,thus avoiding severe blood loss and reducing maternal morbidity and mortality. Carbetocin asynthetic analogue of oxytocin is currently indicated for prevention of uterine atony afterdelivery by caesarean section in spinal or epidural anaesthesia.
 The Aim of Study: To see the efficacy and safety of Carbetocin for the prophylaxis of PPHduring caesarean section.Patients and Methods: An open label single arm clinical trial was conducted in the BagerhatSadar Hospital, Bangladesh over a period of six months from May 2017 to October 2017.Ninety patients who had got admitted in Bagerhat Sadar Hospital, undergoing cesareansection at term were selected. Each patient obtained a single dose of 100 microgramcarbetocin intravenously during cesarean section, immediately after the delivery of the babyand prior to the delivery of the placenta. Outcome measures such as primary PPH, bloodloss was observed and measured by weighing sanitary napkin observed for six hours. Needfor additional uterotonic drug, additional blood transfusion as well as adverse effects were alldocumented.
 Results: Massive blood loss occurred only in 3.3% patients. Among the study population96.7% patients did not need any additional uterotonics. No patient had developed fever,arrhythmia, pulmonary edema, tremor, abdominal pain and pruritus. Only 2.2% had nausea,only 3.3% had hypotention, only 3.3% had vomiting and only 2.2% had headache which wasnot statistically significant. Only 4.4% patients developed PPH.
 Conclusion: Carbetocin appears to be an effective new drug for the prophylaxis of postpartumhemorrhage in cesarean section.
 Bangladesh J Obstet Gynaecol, 2018; Vol. 33(2) : 119-124

Investigating hormone-induced changes in affective state using the affective bias test in male and female rats

Recent clinical and pre-clinical research suggests that affective biases may play an important role in the development and perpetuation of mood disorders. Studies in animals have also revealed that similar neuropsychological processes can be measured in non-human species using behavioural assays designed to measure biases in learning and memory or decision-making. Given the proposed links between hormones and mood, we used the affective bias test to investigate the effects of different hormone treatments in both male and female rats. Animals were pre-treated with acute doses of hormone or vehicle control prior to learning each of two independent substrate-reward associations. During a subsequent choice test, positive or negative biases were observed by animal’s preference towards or away from the substrate learnt during drug treatment respectively. In both sexes, oestradiol and the oestrogen-like compound bisphenol A induced positive biases, whilst blockade of oestrogen hormones with formestane induced a negative bias. Progesterone induced a negative bias in both sexes, but testosterone only induced a negative bias in males. Blocking testosterone with flutamide induced a positive bias in both sexes at the higher dose (10 mg/kg). The oxytocin analogue, carbetocin induced positive biases in both sexes but the vasopressin analogue, desmopressin, induced a positive bias in male rats only. These results provide evidence that modulating levels of hormones using exogenous treatments can induce affective biases in rats. They also suggest that hormone-induced affective biases influence cognitive and emotional behaviour and could have longer-term effects in some mood disorders.

Comparison of the pharmacological profiles of arginine vasopressin and oxytocin analogs at marmoset, macaque, and human vasopressin 1a receptor

Arginine vasopressin (AVP) and oxytocin (OT) are nonapeptides that bind to G-protein coupled receptors and influence social behaviors. Consensus mammalian AVP and OT (Leu8-OT) sequences are highly conserved. In marmosets, an amino acid change in the 8th position of the peptide (Pro8-OT) exhibits unique structural and functional properties. There is ∼85 % structural homology between the OT receptor (OTR) and vasopressin 1a receptor (V1aR) resulting in significant cross-reactivity between the ligands and receptors. Chinese hamster ovary (CHO) cells expressing marmoset (mV1aR), macaque (qV1aR), or human vasopressin receptor 1a (hV1aR) were used to assess AVP, Leu8-OT and Pro8-OT pharmacological profiles. To assess activation of Gq, functional assays were performed using Fluo-3 to measure ligand-induced Ca2+ mobilization. In all three V1aR-expressing cell lines, AVP was more potent than the OT ligands. To assess ligand-induced hyperpolarization, FLIPR Membrane Potential (FMP) assays were performed. In all three V1aR lines, AVP was more potent than the OT analogs. The distinctive U-shaped concentration-response curve displayed by AVP may reflect enhanced desensitization of the mV1aR and hV1aR, which is not observed with qV1aR. Evaluation of Ca2+-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Taken together, these data suggest differences in ligand-receptor signaling that may underlie differences in social behavior. Integrative studies of behavior, genetics and ligand-receptor interaction will help elucidate the connection between receptor pharmacology and social behaviors.

Monolithic and core-shell particles stationary phase morphologies in protein analysis; peptide mapping of erythropoietin hormone and determination of carbetocin

Chromatographic application of two recent HPLC stationary phases for protein analysis was demonstrated. These two stationary phases are namely monolithic rods and core-shell particles. Monolithic rods have higher permeability and larger porous structure allowing faster elution, while smaller core-shell particles have narrower particle size distribution and better packing allowing larger number of resolved peptides. Peptide mapping of erythropoietin hormone, which is used in the treatment of symptomatic anaemia associated with chronic renal failure in adult and pediatric patients, was carried out on monolithic column and core-shell particles. Comparison between the effectiveness of separation on both columns was established and the new morphologies proved their capability of replacing the totally porous particles with higher resolution power at shorter analysis time. Carbetocin is an oxytocin analogue with a longer duration of action that stimulates uterine contraction and milk ejection in mammals. Monolithic column was also applied for quantitative HPLC analysis of carbetocin using ethanol as cheap and greener alternative organic modifier without compromise to a full impurity profiling. The proposed method was validated concerning with accuracy, precision, robustness, sensitivity, limits of detection and quantitation and proved to be green and stability indicating.

Comparison of the pharmacologic profiles of arginine vasopressin and oxytocin analogs at marmoset, titi monkey, macaque, and human oxytocin receptors

The oxytocin-arginine vasopressin (OT-AVP) ligand-receptor family influences a variety of physiological, behavioral, and social behavioral processes in the brain and periphery. The OT-AVP family is highly conserved in mammals, but recent discoveries have revealed remarkable diversity in OT ligands and receptors in New World Monkeys (NWMs) providing a unique opportunity to assess the effects of genetic variation on pharmacological signatures of peptide ligands. The consensus mammalian OT sequence has leucine in the 8th position (Leu8-OT), whereas a number of NWMs, including the marmoset, have proline in the 8th position (Pro8-OT) resulting in a more rigid tail structure. OT and AVP bind to OT’s cognate G-protein coupled receptor (OTR), which couples to various G-proteins (Gi/o, Gq, Gs) to stimulate diverse signaling pathways. CHO cells expressing marmoset (mOTR), titi monkey (tOTR), macaque (qOTR), or human (hOTR) OT receptors were used to compare AVP and OT analog-induced signaling. Assessment of Gq-mediated increase in intracellular calcium (Ca2+) demonstrated that AVP was less potent than OT analogs at OTRs from species whose endogenous ligand is Leu8-OT (tOTR, qOTR, hOTR), relative to Pro8-OT. Likewise, AVP-induced membrane hyperpolarization was less potent at these same OTRs. Evaluation of (Ca2+)-activated potassium (K+) channels using the inhibitors apamin, paxilline, and TRAM-34 demonstrated that both intermediate and large conductance Ca2+-activated K+ channels contributed to membrane hyperpolarization, with different pharmacological profiles identified for distinct ligand-receptor combinations. Understanding more fully the contributions of structure activity relationships for these peptide ligands at vasopressin and OT receptors will help guide the development of OT-mediated therapeutics.

153 The effects of parity and oxytocin or prostaglandin F2α added to insemination doses on reproductive performance of pigs bred in summer

Summer is the least favourable season for swine reproduction, mainly due to long photoperiods and heat stress. Such conditions negatively impinge on the reproductive system of sows and boars, manifesting in debilitated uterine and gonadal function. This situation is exacerbated by the dilution of ejaculates in semen extender before AI. Consequently, there is a noticeable decline in piglet productivity of summer-breeding gilts and sows. The main goal of this study was to determine the effect of oxytocin (OX) or prostaglandin F2α analogue (PG) added to boar semen extender on the duration of insemination and reproductive performance of pigs bred in July and August. A total of 144 females (80 gilts and second-parity sows (G+SP) and 64 multiparous sows (M)) were divided into three groups (n=48 per group). The OX (11 G+SP and 37M) and PG (20 G+SP and 28M) groups were inseminated twice (at the onset of behavioural oestrus and 22-24h later) using semen supplemented with 20IU of OX or 5mg of PG, respectively; the controls (33 G+SP and 15M) were artificially inseminated with non-supplemented inseminate doses. Pregnancy was detected ultrasonographically on gestational day 42, and the number and viability of piglets were recorded at farrowing. Proportions were analysed using chi-square test (Brandt and Snedecor formula), and other numerical data were analysed using two-way analysis of variance and least significant difference test to determine the differences between individual mean values (SigmaPlot, Systat Software Inc.). The mean duration of first insemination was shorter (P<0.05) in M females (80±22s) compared with G+SP females (191±26s) inseminated with PG-supplemented semen, whereas the second insemination was shorter (P<0.05) in M females than in G+SP females artificially inseminated with OX-supplemented semen (93±15s compared with 192±28s). The mean pregnancy rate was lower (P<0.05) in control G+SP females (26/33; 85%) than in OX G+SP females (11/11; 100%). The farrowing rate was less (P<0.05) in control females (36/48; 75%) than in OX females (44/48; 92%), and it was less (P<0.05) in PG G+SP females (14/20; 70%) compared with PG M females (26/28; 93%). The M females in the OX group had more (P<0.05) stillborn piglets per litter compared with their G+SP counterparts (0.6±0.1 vs. 0.1±0.1). Overall, PG females had more (P<0.05) weak piglets per litter (1.2±0.2) compared with the control (0.5±0.2) and OX (0.6±0.2) groups. The present results reveal the occurrence of both beneficial and undesirable effects of PG and OX added to boar semen extender on reproductive performance of breeding pigs in summer. Addition of PG was associated with shorter first-insemination times in older sows compared with G+SP animals but also with lower farrowing rates in younger animals and an overall increase in the number of weak piglets at farrowing. Supplementation of OX was in turn associated with a shorter second insemination and higher pregnancy rates in young females but more stillborn piglets per litter in multiparous sows. The specific causative mechanisms of these associations remain to be elucidated.

Synthesis of oxytocin derivatives lipidated via a carbonate or carbamate linkage as a long-acting therapeutic agent for social impairment-like behaviors

In the course of our studies of hydrophobic oxytocin (OT) analogues, we newly synthesized lipidated OT (LOT-4a-c and LOT-5a-c), in which a long alkyl chain (C14-C16) is conjugated via a carbonate or carbamate linkage at the Tyr-2 phenolic hydroxy group and a palmitoyl group at the terminal amino group of Cys-1. These LOTs did not activate OT and vasopressin receptors. Among the LOTs, however, LOT-4c, having a C16-chain via a carbonate linkage at the phenolic hydroxyl group of the Tyr-2, showed very long-lasting action for the recovery of impaired social behavior in CD38 knockout mice, a rodent model of autistic phenotypes, whereas the effect of OT itself rapidly diminished. These results indicate that LOT-4c may serve as a potential prodrug in mice.

Long-Acting and Selective Oxytocin Peptide Analogs Show Antidiabetic and Antiobesity Effects in Male Mice.

Oxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control and lipid metabolism in several species, including humans, monkeys, and rodents. However, OXT’s short half-life in circulation and lack of receptor selectivity limit its application and efficacy. In this study, we report an OXT peptide analog (OXTGly) that is potent and selective for the OXT receptor (OXTR). OXT, but not OXTGly, activated vasopressin receptors in vitro and acutely increased blood pressure in vivo when administered IP. OXT suppressed food intake in mice, whereas OXTGly had a moderate effect on food intake when administered IP or intracerebroventricularly. Both OXT (IP) and OXTGly (IP) improved glycemic control in glucose tolerance tests. Additionally, both OXT (IP) and OXTGly (IP) stimulated insulin, glucagon-like peptide 1, and glucagon secretion in mice. We generated lipid-conjugated OXT (acylated-OXT) and OXTGly (acylated-OXTGly) and demonstrated that these molecules have significantly extended half-lives in vivo. Compared with OXT, 2-week treatment of diet-induced obese mice with acylated-OXT [subcutaneous(ly) (SC)] resulted in enhanced body weight reduction, an improved lipid profile, and gene expression changes consistent with increased lipolysis and decreased gluconeogenesis. Treatment with acylated-OXTGly (SC) also resulted in a statistically significant weight loss, albeit to a lesser degree compared with acylated-OXT treatment. In conclusion, we demonstrate that selective activation of the OXTR pathway results in both acute and chronic metabolic benefits, whereas potential activation of vasopressin receptors by nonselective OXT analogs causes physiological stress that contributes to additional weight loss.

Making a long-lasting version of oxytocin

Challenges with social interactions can accompany depression, schizophrenia, and autism spectrum disorders. Some researchers think cell-signaling problems involving oxytocin—the peptide hormone responsible for social bonding—might be a contributing factor. The therapeutic potential of oxytocin, however, is difficult to study, since the hormone breaks down quickly in the body. In a new study, researchers have shown that two longer-lasting oxytocin analogs can affect social functioning for up to 24 h in mice genetically engineered to have autism- or depression-like characteristics (J. Med. Chem. 2019, DOI: 10.1021/acs.jmedchem.8b01691). Haruhiro Higashida of Kanazawa University, Satoshi Shuto of Hokkaido University, and colleagues synthesized oxytocin analogs that had either N-(p-fluorobenzyl)glycine or N-(3-hydroxypropyl)glycine replacing a proline on the oxytocin backbone. They then measured the compounds’ lifetime in mice that had a genetic mutation impairing oxytocin signaling. Oxytocin’s effect, determined by performance on tests demonstrating nurturing or depression-like behavior, disappeared after about 6 h. But the fluorobenzyl analog

Effects of oxytocin and carbetocin on farrowing performance

During sow parturition, there is need for an alternative uterotonic to oxytocin with less potency so piglets are not at risk of hypoxia and stillbirth. In this study, there was examination of carbetocin, a longer lasting analogue of oxytocin, and whether the lesser contractile force and duration resulting as a consequence of this treatment would improve piglet survivability. Following delivery of the first piglet, sows were serially assigned by parity to receive injections of 10 IU oxytocin (n = 35), 0.07 mg carbetocin (n = 36), or serve as a non-injected control (n = 30). The incidence of dystocia and stillbirths was recorded. To estimate liveborn piglet viability, umbilical cord blood samples were obtained from pigs 1, 2, 3 and 8, 9, 10, and lactate content was quantified to assess hypoxia during delivery. A blood sample collected at 24 h was assayed for total protein in plasma (%) as an indicator of colostrum intake. Treatment with oxytocin and carbetocin reduced farrowing duration (P = 0.023) and sows treated with carbetocin had piglets with the least umbilical cord blood lactate (P = 0.008) and plasma protein (P = 0.005) concentrations. These data indicate carbetocin has the efficacy to accelerate piglet delivery and reduce piglet hypoxia, although the reason for reduced plasma protein with this treatment remains unexplained.

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors.

The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro7 of OT was replaced with N-( p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist ( EMax = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16-24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.

Design of Oxytocin Analogs.

The neurohypophyseal hormone oxytocin (OT) and related modulators of the oxytocin receptor (OTR) have been the subject of intensive research for nearly seven decades. Despite having rather poor drug-like properties, OT is used as a treatment for labor induction, postpartum hemorrhage, and lactation support. The potential use of OT in the treatment of central nervous system (CNS)-related diseases has recently renewed interest in the pharmacology of OT. Oxytocin is one of the most extensively studied cyclic peptides and since the elucidation of its structure in 1953 thousands of peptidic OT analogs with antagonistic and agonistic properties have been synthesized and biologically evaluated. Among them are atosiban, a mixed oxytocin receptor (OTR)/vasopressin 1a receptor (V1aR) antagonist used as a tocolytic agent approved (in certain countries), and carbetocin, a longer acting OTR agonist on the market for the treatment of postpartum hemorrhage. Many other OT analogs with improved pharmacological properties (e.g., barusiban, Antag III) have been identified. These peptides have been tested in clinical trials and/or used as pharmacological tools. In this chapter, the modifications of the OT molecule that led to the discovery of these compounds are reviewed.

Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism

Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4–9) and OT(5–9). While OT(5–9) failed to affect social deficits, the metabolite OT(4–9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4–9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.

Oxytocin analog may save moms’ lives

After a mother gives birth to a healthy baby, she’s far from out of dangers. Losing too much blood postpartum accounts for about 70,000 deaths worldwide every year, with 99% of deaths occurring in developing nations. Doctors can prevent excessive bleeding by administering oxytocin, a drug and naturally occurring hormone. But oxytocin, a peptide, degrades after prolonged heat exposure, so the drug is not reliable in nations lacking consistently climate-controlled hospitals and refrigerated supply chains. Now, the World Health Organization (WHO) is reporting that a heat-stable formulation of an oxytocin analog—carbetocin—is an effective way around the problem (N. Engl. J. Med. 2018, DOI: 10.1056/NEJMoa1805489). “This is one of the most important public health issues for women in the developing world,” says Jeffrey M. Smith, an obstetrician-gynecologist at Jhpiego, an international health nonprofit group, who was not involved with the study. “And it’s solved by using chemistry.” Carbetocin is not a

Discovery of peptide probes to modulate oxytocin-type receptors of insects

The oxytocin/vasopressin signalling system is conserved across the animal kingdom. In insects, the role of oxytocin-type (inotocin) neuropeptides has only been studied in locusts, beetles and ants, but their physiology continues to be poorly understood. One reason for this knowledge deficit is the lack of available research tools to complement functional genomics efforts. Consequently, ligands to probe insect inotocin receptors are essential. In this study, we sought to identify novel agonists and antagonists of the inotocin receptor from the representative model species Tribolium castaneum and Lasius niger. Drawing upon known ligands of the human receptors, we examined the pharmacology of the plant-derived cyclotide kalata B7 and the synthetic oxytocin analogue atosiban. Kalata B7 is a weak partial agonist of both inotocin receptors. This is the first reported direct interaction of cyclotides with an insect receptor, an observation that may explain their presumed role in herbivore defence. Furthermore, we discovered atosiban is an antagonist of the Tribolium receptor, which may provide a useful probe to investigate the functionality of inotocin signalling in beetles and related insect species. Our findings will enable further examination of insect inotocin receptor pharmacology and physiology, and may trigger studies to comprehend the interaction of plant cyclotides and insects.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.