{
  "abstract": "Orexin receptor 2 (OX2R)-selective agonists have potent wake-promoting effects and could be a promising treatment for sleep/wake disorders, such as narcolepsy type 1. However, OX2R agonists may cause cardiovascular (CV) adverse events. In this study, we explored strategies to minimize CV side effects while preserving the wake-promoting efficacy of OX2R-selective agonists, OX-202 and OX-203, in rats. CV parameter analyses using a telemetry system in unrestrained rats revealed that both OX-202 and OX-203 induced elevated blood pressure, which correlated with their central exposure levels. Moreover, in electrophysiological analyses in rat brain slices, OX-202 activated neurons in the rostral ventrolateral medulla, a key brain area regulating CV function, suggesting that CV effects of OX2R agonists may be centrally mediated. A steep increase in plasma OX-202 levels induced immediate wakefulness but elevated blood pressure. A gradual rise in OX-202 plasma levels resulted in delayed wakefulness without blood pressure elevation. Non-awakening and low-level preexposure for 1 h, followed by a steep increase in OX-202 plasma levels, achieved prompt wakefulness without blood pressure elevation. These results highlight that the pharmacokinetic profile is a critical factor for OX2R agonists in achieving potent and prompt wakefulness with a lower risk of blood pressure increase.",
  "abstract_shown": true,
  "affiliations": [
    "Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited",
    "Drug Metabolism, Pharmacokinetics and Modeling, Data and Quantitative Sciences, Takeda Pharmaceutical Company Limited",
    "Global Chemistry, Research, Takeda Pharmaceutical Company Limited"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ako Kato"
    },
    {
      "affs": [
        1
      ],
      "name": "Masanori Nakakariya"
    },
    {
      "affs": [
        2
      ],
      "name": "Tatsuki Koike"
    },
    {
      "affs": [
        0
      ],
      "name": "Haruhide Kimura"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3vk1sxqf0d4w5.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-64372-4",
  "fulltext_url": "https://doi.org/10.1038/s41598-026-64372-4",
  "id": "3vk1sxqf0d4w5",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://doi.org/10.1038/s41598-026-64372-4",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "Q"
    ],
    [
      "lcc",
      "R"
    ],
    [
      "openalex",
      "2805|Sleep and Wakefulness Research"
    ]
  ],
  "openalex": "W7201861990",
  "pdf_url": "https://www.nature.com/articles/s41598-026-64372-4_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/3vk1sxqf0d4w5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:45:57Z",
      "native_id": "3ad2580e54534719b19da6ab2c895c86",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41598-026-64372-4"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2805|Sleep and Wakefulness Research",
      "subfield": "neuroscience"
    }
  ],
  "title": "Mitigation of cardiovascular adverse effects while preserving wake-promoting efficacy of orexin receptor 2 − selective agonists",
  "title_text": "Mitigation of cardiovascular adverse effects while preserving wake-promoting efficacy of orexin receptor 2 − selective agonists",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:45:57Z",
  "url": "https://research.draconitic.com/paper/3vk1sxqf0d4w5",
  "venue": "Scientific Reports",
  "versions": []
}