Nonpeptide oxytocin antagonists: Analogs of L-371,257 with improved potency

Williams, Peter; Bock, Mark G.; Evans, B.; Freidinger, Roger; Gallicchio, Steven N.; Guidotti, Maribeth T.; Jacobson, Marlene A.; Kuo, Michelle S.; Levy, Michelle R.; Lis, Edward; Michelson, Stuart R.; Pawluczyk, Joseph; Perlow, Debra S.; Pettibone, Douglas J.; Quigley, Amy G.; Reiss, Duane R.; Salvatore, Christopher; Stauffer, Kenneth J.; Woyden, Carla J.

doi:10.1016/s0960-894x(99)00181-x

Cited by 17 publications

(9 citation statements)

References 10 publications

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“…26 It should be noted that L-371,257 can also act on V1A in the rat. 27 However, in our study, L-371,257 did not mimic the effects of the V1A antagonist, and so we interpret our data to suggest that effects of L-371,257 were due to blockade of OTR, and that V1A and OTR mediate differential effects of AVP in the amygdala (CeA).…”

Section: Discussioncontrasting

confidence: 63%

Differential contributions of vasopressin V1A and oxytocin receptors in the amygdala to pain-related behaviors in rats

Cragg

Neugebauer

2016

Mol Pain

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Neuroplastic changes in the amygdala account for emotional-affective aspects of pain and involve neuropeptides such as calcitonin gene-related peptide and corticotropin-releasing factor. Another neuropeptide system, central arginine vasopressin, has been implicated in neuropsychiatric disorders, but its role in pain-related emotional expression and neuroplasticity remains to be determined. Here, we tested the hypothesis that arginine vasopressin in the amygdala contributes to pain-related emotional-affective responses, using stereotaxic applications of arginine vasopressin and antagonists for G-protein coupled vasopressin V1A and oxytocin receptors in adult male Sprague-Dawley rats. In normal animals, arginine vasopressin increased audible and ultrasonic vocalizations and anxiety-like behavior (decreased open-arm preference in the elevated plus maze). The facilitatory effects were blocked by a selective V1A antagonist (SR 49059, Relcovaptan) but not by an oxytocin receptor antagonist (L-371,257). L-371,257 had some facilitatory effects on vocalizations. Arginine vasopressin had no effect in arthritic rats (kaolin/carrageenan knee joint pain model). SR 49059 inhibited vocalizations and anxiety-like behavior (elevated plus maze) in arthritic, but not normal, rats and conveyed anxiolytic properties to arginine vasopressin. Arginine vasopressin, SR 49059, and L-371,257 had no significant effects on spinal reflexes. We interpret the data to suggest that arginine vasopressin through V1A in the amygdala contributes to emotional-affective aspects of pain (arthritis model), whereas oxytocin receptors may mediate some inhibitory effects of the vasopressin system.

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Section: Discussioncontrasting

confidence: 63%

Differential contributions of vasopressin V1A and oxytocin receptors in the amygdala to pain-related behaviors in rats

Cragg

Neugebauer

2016

Mol Pain

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“…Additionally, this methodology eliminated the use of highly toxic thallium nitrate which was included in a previously reported synthetic pathway of a similar molecule. 22 It should also be noted that the use of thallium nitrate was originally implemented in our synthetic pathway, but the resulting yields were extremely lower than what literature reported—including complete failures in multiple trials. Acetic acid 9 was then reacted with quinolinone 10 via condensation in the presence of hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and Hünig’s base to give 11 in good yields.…”

Section: Resultsmentioning

confidence: 87%

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Smith

Freeman²,

Stehouwer

et al. 2012

Bioorganic & Medicinal Chemistry

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Compounds 1–4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1–4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1–4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [125I]1 and [125I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [125I]1 and [125I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [18F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [18F]3 and [11C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates.

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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: Analogs of L-371,257 with improved potency

Cited by 17 publications

References 10 publications

Differential contributions of vasopressin V1A and oxytocin receptors in the amygdala to pain-related behaviors in rats

Differential contributions of vasopressin V1A and oxytocin receptors in the amygdala to pain-related behaviors in rats

Synthesis and evaluation of C-11, F-18 and I-125 small molecule radioligands for detecting oxytocin receptors

Preterm Labour: An Overview of Current and Emerging Therapeutics

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