Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder

Schnider, Patrick; Bissantz, Caterina; Bruns, Andreas; Dolente, Cosimo; Goetschi, Erwin; Jakob‐Roetne, Roland; Künnecke, Basil; Mueggler, Thomas; Muster, Wolfgang; Parrott, Neil; Pinard, Emmanuel; Ratni, Hasane; Risterucci, Céline; Rogers‐Evans, Mark; Kienlin, Markus von; Grundschober, Christophe

doi:10.1021/acs.jmedchem.9b01478

Cited by 46 publications

(39 citation statements)

References 46 publications

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“…26 Further, the triazolobenzodiazepine, balovaptan (RG7314) showed encouraging results for the treatment of ASD in a clinical phase II study, which led to a Breakthrough Therapy Designation by the U.S. FDA in January 2018. 27 Despite these encouraging preclinical findings, the potential of V1A antagonists for the treatment of cardiovascular and immune-mediated diseases is largely unexplored. This has, at least in part, been attributed to the lack of appropriate tools for in vivo imaging of V1A receptors in peripheral organs.…”

Section: Introductionmentioning

confidence: 99%

Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging

Haider¹,

Xiao²,

Xia

et al. 2021

Preprint

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Objectives: Vasopressin 1A (V1A) receptors have been linked to autism spectrum disorder, heart failure, diabetes and renal disease. Currently, there is a lack of validated probes for clinical V1A-targeted imaging and previous PET studies have primarily focused on the brain. To enable non-invasive real-time quantification of V1A receptors in peripheral organs, we sought to develop a suitable PET radioligand that would allow specific and selective V1A receptor imaging in vivo. Methods: The previously reported triazolobenzodiazepine-based V1A antagonist, PF-184563, served as a structural basis for the development of a suitable V1A-targeted PET probe. Initially, PF-184563 and the respective desmethyl precursor for radiolabeling were synthesized via multistep organic synthesis. Inhibitory constants of PF-184563 for V1A, V1B, V2 and oxytocin (OT) receptors were assessed by competitive radioligand binding or fluorescent-based assays. Molecular docking of PF-184563 to the V1A receptor binding pocket was performed to corroborate the high binding affinity, while carbon-11 labeling was accomplished via radiomethylation. To assess the utility of the resulting PET radioligand, [11C]17, cell uptake studies were performed in a human V1A receptor Chinese hamster ovary (CHO) cell line under baseline and blockade conditions, using a series of V1A, V1B and V2 antagonists in >100-fold excess. Further, to show in vivo specificity, we conducted PET imaging and biodistribution experiments, thereby co-administering the clinical V1A-antagonist, balovaptan (3mg/kg), as a blocking agent. Results: PF-184563 and the respective desmethyl precursor were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. A subnanomolar inhibitory constant (Ki) of 0.9 nM towards the V1A receptor was observed for PF-184563, while the triazolobenzodiazepine derivative concurrently exhibited excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM). [11C]17 was obtained in high radiochemical purity (> 99%), molar activities ranging from 37 - 46 GBq/μmol and a non-decay-corrected radiochemical yield of 8%. Cell uptake studies revealed considerable tracer binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. PET imaging and biodistribution studies in CD-1 mice indicated specific tracer binding in the thyroid, pancreas, spleen and the heart. Conclusion: We report the development of a V1A-targeted PET radioligand that is suitable for subtype-selective in vitro and in vivo receptor imaging. Indeed, [11C]17 proved to specifically visualize V1A receptors in several organs including the heart, pancreas, spleen and thyroid. These results suggest that [11C]17 can be a valuable tool to study the role of V1A receptors in cardiovascular and immune-mediated pathologies.

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Section: Introductionmentioning

confidence: 99%

Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging

Haider¹,

Xiao²,

Xia

et al. 2021

Preprint

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“…Vasopressin (AVP) and oxytocin have been implicated in the etiology of psychiatric disorders, such as schizophrenia [1], autism [2][3][4], and depression [5]. AVP acts centrally within the central nervous system (CNS) where it modulates a range of behaviors from learning and memory and responses to stressors to social behaviors [6].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, a study by Ferris et al [10] suggested that V 1A receptor antagonists may be used to treat interpersonal violence co-occurring with an illness such as attention-deficit/hyperactivity disorder, autism, bipolar disorder, and substance abuse. Therefore, it is hypothesized that antagonistic action on the V 1A receptor might attribute to the treatment approach in anxiety-like behavior and recently, discovery of a potent, selective, and brain penetrant V 1A receptor antagonist is emerging [4,11]. Additionally, AVP had been reported to mediate brain edema formation and cerebral ischemia by regulating water permeability in astrocytes [12].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported previously that AVP is released in response to peripheral inflammation [20,21] which is deleterious to various immune-mediated diseases. A recent report on the Phase II clinical trial of a selective V 1A R antagonist balovaptan suggested it as a potential treatment for the socialization and communication deficits in autism spectrum disorder [4,22]. Likewise, investigations on the functional role of V 1A R in cardiovascular homeostasis using gene targeting demonstrated lower basal blood pressure in mutant mice lacking the V 1A R gene (V 1A −/− ) compared to the wild-type mice (V 1A +/+ ) [18,23].…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effect of Aurantio-Obtusin, a Putative Vasopressin V1A Receptor Antagonist, on Transient Forebrain Ischemia Mice Model

Paudel

Kim

Jeon

et al. 2021

IJMS

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Traditional Chinese medicines (TCMs) have been a rich source of novel drug discovery, and Cassia seed is one of the common TCMs with numerous biological effects. Based on the existing reports on neuroprotection by Cassia seed extract, the present study aims to search possible pharmacological targets behind the neuroprotective effects of the Cassia seeds by evaluating the functional effect of specific Cassia compounds on various G-protein-coupled receptors. Among the four test compounds (cassiaside, rubrofusarin gentiobioside, aurantio-obtusin, and 2-hydroxyemodin 1-methylether), only aurantio-obtusin demonstrated a specific V1AR antagonist effect (71.80 ± 6.0% inhibition at 100 µM) and yielded an IC50 value of 67.70 ± 2.41 μM. A molecular docking study predicted an additional interaction of the hydroxyl group at C6 and a methoxy group at C7 of aurantio-obtusin with the Ser341 residue as functional for the observed antagonist effect. In the transient brain ischemia/reperfusion injury C57BL/6 mice model, aurantio-obtusin attenuated the latency time that was reduced in the bilateral common carotid artery occlusion (BCCAO) groups. Likewise, compared to neuronal damage in the BCCAO groups, treatment with aurantio-obtusin (10 mg/kg, p.o.) significantly reduced the severity of damage in medial cornu ammonis 1 (mCA1), dorsal CA1, and cortex regions. Overall, the findings of this study highlight V1AR as a possible target of aurantio-obtusin for neuroprotection.

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“…Intranasal OXT has been found to improve social behaviour deficits in autistic adolescents-a promising result (LeClerc & Easley, 2015;Parker et al, 2017). The pharmacological investigation into the role of the vasopressin 1a receptor (V1a) in the improvement of social-communicative abilities found that its inhibition improved social deficits and social living skills (Bolognani et al, 2019;Schnider et al, 2020). Balovaptan, an orally administered V1a receptor antagonist is currently undergoing phase 3 clinical trials for the treatment of adults (ClinicalTrials.gov, 2020a) and phase 2 for the treatment of children (ClinicalTrials.gov, 2020b).…”

Section: Treatmentmentioning

confidence: 99%

An Immune Rat Model of Autism: Does Environmental Enrichment Alter Higher Social Functioning?

Wilkin-Krug¹

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The neurodevelopmental condition autism spectrum disorder (ASD) is marked by impaired communication, impaired social interaction, and repetitive or restricted behaviours (American Psychiatric Association, 2013). ASD is caused by a combination of genetic and environmental factors, including maternal infection during pregnancy. There are no pharmacological treatment options for ASD, but environmental enrichment (EE) is a promising alternative to rehabilitate or prevent related symptoms. Patients with ASD often have a deficit in higher social abilities, including prosociality, but to date, no rat studies have investigated how EE affects higher social functions in the context of ASD. Therefore, this thesis investigated the effect of EE on higher social functions in an in vivo rodent model of ASD. Using a two-by-two factorial design, pregnant Sprague Dawley rats received either saline or the viral mimic polyinosinic-polycytidylic acid (poly I:C) to trigger an immune reaction and were placed in either standard or enriched housing. In the enrichment groups, pups received pre-weaning enrichment sessions while animals in the standard-housing groups were left undisturbed until weaning. I assessed the animals’ neonatal communication, general sociability and social novelty behaviour, prosocial tendencies, and locomotor activity. The main hypothesis I investigated was that the maternal immune reaction would disrupt fetal neural development and alter communication and social behaviours in the offspring and that EE would reduce or reverse these deficits. There was a transient poly I:C effect on neonatal communication early on, but the treatment did not cause long-term social deficits. Poly I:C also affected adult locomotor activity but did neither reduce sociability nor prosociality. As the very weak treatment effects did not result in clear deficits, EE could not lead to improvements. While the findings did not offer insight into the enrichment effect on impaired prosocial behaviours, this was likely due to methodological issues and limitations. Future ASD research should address these concerns to further the understanding of how environmental adjustments can stimulate the impaired social parts of the brain to redirect the atypical developmental trajectory towards a more typical one.

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Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder

Cited by 46 publications

References 46 publications

Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging

Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging

Neuroprotective Effect of Aurantio-Obtusin, a Putative Vasopressin V1A Receptor Antagonist, on Transient Forebrain Ischemia Mice Model

An Immune Rat Model of Autism: Does Environmental Enrichment Alter Higher Social Functioning?

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