Nonpeptide oxytocin antagonists: Potent, orally bioavailable analogs of L-371,257 containing A 1-R-(pyridyl)ethyl ether terminus

Kuo, Michelle S.; Bock, Mark G.; Freidinger, Roger; Guidotti, Maribeth T.; Lis, Edward; Pawluczyk, Joseph; Perlow, Debra S.; Pettibone, Douglas J.; Quigley, Amy G.; Reiss, Duane R.; Williams, Peter; Woyden, Carla J.

doi:10.1016/s0960-894x(98)00568-x

Cited by 16 publications

(5 citation statements)

References 10 publications

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“…Pre‐treatment with the oxytocin receptor antagonist L‐371,257 (10 −7 M) (Kuo et al . ) or with the antagonist of melanocortin receptors type 3/4, SHU 9119 (10 −7 M) (Tanida and Mori ), did not significantly affect the increase in [Ca 2+ ] i produced by nesfatin‐1 (10 −6 M): Δ[Ca 2+ ] i = 376 ± 4.9 nM in the absence of the antagonists, versus 358 ± 6.3 nM in the presence of L‐371,257 or 349 ± 5.7 nM in the presence of SHU 9119 ( n = 6 for each treatment) (Fig. b).…”

Section: Resultsmentioning

confidence: 99%

Nesfatin‐1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats

Brailoiu

Deliu

Tica

et al. 2013

Journal of Neurochemistry

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Nesfatin-1, a peptide whose receptor is yet to be identified, has been involved in the modulation of feeding, stress and metabolic responses. More recently, increasing evidence supports a modulatory role for nesfatin-1 in autonomic and cardiovascular activity. This study was undertaken to test if the expression of nesfatin-1 in the nucleus ambiguus, a key site for parasympathetic cardiac control, may be correlated with a functional role. Since we have previously demonstrated that nesfatin-1 elicits Ca2+ signaling in hypothalamic neurons, we first assessed the effect of this peptide on cytosolic Ca2+ in cardiac preganglionic neurons of nucleus ambiguus. We provide evidence that nesfatin-1 increases cytosolic Ca2+ concentration via a Gi/o-coupled mechanism. The nesfatin-1-induced Ca2+ rise is critically dependent on Ca2+ influx via P/Q-type voltage-activated Ca2+ channels. Repeated administration of nesfatin-1 leads to tachyphylaxis. Further, nesfatin produces a dose-dependent depolarization of cardiac vagal neurons via a Gi/o-coupled mechanism. In vivo studies, using telemetric and tail-cuff monitoring of heart rate and blood pressure, indicate that microinjection of nesfatin-1 into the nucleus ambiguus produces bradycardia not accompanied by a change in blood pressure in conscious rats. Taken together, our results identify for the first time that nesfatin-1 decreases heart rate by activating cardiac vagal neurons of nucleus ambiguus.

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Section: Resultsmentioning

confidence: 99%

Nesfatin‐1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats

Brailoiu

Deliu

Tica

et al. 2013

Journal of Neurochemistry

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“…Therefore, we adopted a complementary strategy in which an oxytocin receptor antagonist, L-371,257, was intraperitoneally administered to male animals. We chose this specific antagonist because it is unable to cross the blood-brain www.nature.com/scientificreports/ barrier 65 , and therefore its consequences on VNO activity could be unequivocally assigned to direct manipulation of the sensory interface. We injected L-371,257 in dpc15 mice, which exhibit naturally reduced pup-induced VNO activity after the male's contact with the female.…”

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confidence: 99%

Peripheral oxytocin injection modulates vomeronasal sensory activity and reduces pup-directed aggression in male mice

Nakahara¹,

Camargo²,

Magalhães³

et al. 2020

Sci Rep

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Behaviors are shaped by hormones, which may act either by changing brain circuits or by modifying sensory detection of relevant cues. Pup-directed behaviors have been previously shown to change via action of hormones at the brain level. Here, we investigated hormonal control of pup-induced activity in the vomeronasal organ, an olfactory sensory structure involved in the detection of non-volatile chemosignals. Vomeronasal activity decreases as males switch from a pup-aggressive state to a non-aggressive parenting state, after they socially contact a female. RNA sequencing, qPCR, and in situ hybridization were used to identify expression, in the vomeronasal sensory epithelium, of candidate GPCR hormone receptors chosen by in silico analyses and educated guesses. After identifying that oxytocin and vasopressin receptors are expressed in the vomeronasal organ, we injected the corresponding hormones in mice and showed that oxytocin administration reduced both pup-induced vomeronasal activity and aggressive behavior. Conversely, injection of an oxytocin receptor antagonist in female-primed male animals, which normally exhibit reduced vomeronasal activity, significantly increased the number of active vomeronasal neurons. These data link oxytocin to the modulation of olfactory sensory activity, providing a possible mechanism for changes in male behavior after social experience with females.

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“…Striving, as usual, for superior quality, Merck continued the compound optimisation program, with the aim of further improving pharmacokinetic half-life, solubility, potency, and bioavailability. Several new compounds have emanated from these efforts, the most prominent being 32 [275] and 33 [276], as well as others, such as 34 [277]. Especially compound 32, or L-372,662, shows an impressive overall profile, in combining the positive features of L-371,257 with improved physicochemical and pharmacokinetic properties [278].…”

Section: Non-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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Nonpeptide oxytocin antagonists: Potent, orally bioavailable analogs of L-371,257 containing A 1-R-(pyridyl)ethyl ether terminus

Cited by 16 publications

References 10 publications

Nesfatin‐1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats

Nesfatin‐1 activates cardiac vagal neurons of nucleus ambiguus and elicits bradycardia in conscious rats

Peripheral oxytocin injection modulates vomeronasal sensory activity and reduces pup-directed aggression in male mice

Preterm Labour: An Overview of Current and Emerging Therapeutics

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