{
  "abstract": "A series of 2,5,7-trisubstituted [1,2,4]triazolo[1,5-a][1,3,5]triazines (TTs) was developed to identify selective A₃ AR antagonists. Guided by previous structure-activity relationship studies, the C2-furyl substituent was replaced with phenyl or 4-methoxyphenyl moieties to improve A₃ AR affinity and selectivity. C2 phenyl substitution, together with appropriate C5 and C7 amino substituents, critically modulates receptor recognition. In particular, benzylamino substitution at C5 markedly enhanced A₃ AR affinity, yielding compound 15 as the most potent antagonist of the series (Ki = 0.485 nM), whereas incorporation of a 4-methoxyphenyl group at C2 substantially improved subtype selectivity, exemplified by compound 30 (>2800-fold selective for A₃ AR). Molecular docking at the recently determined antagonist-bound structure of the A₃ AR rationalized these trends and identified key structural determinants of A₃ AR preference. The biological relevance of A₃ AR blockade was investigated in rat hippocampal slices subjected to oxygen-glucose deprivation. Compound 15 delayed anoxic depolarization and, when administered during ischemia, prevented its onset in most slices and promoted near-complete recovery of synaptic transmission. These findings identify TT derivatives as promising and highly selective A₃ AR antagonists with potential neuroprotective applications in cerebral ischemia.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy.",
    "Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.",
    "Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.",
    "Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.",
    "Institut für Pharmakologie und Toxikologie, University of Würzburg, Würzburg, Germany."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Veronika Kost"
    },
    {
      "affs": [
        0
      ],
      "name": "Filippo Prencipe"
    },
    {
      "affs": [
        1
      ],
      "name": "Federica Panozzi",
      "orcid": "0009-0000-6850-5097"
    },
    {
      "affs": [
        2
      ],
      "name": "Veronica Salmaso"
    },
    {
      "affs": [
        3
      ],
      "name": "Sonja Kachler"
    },
    {
      "affs": [
        4
      ],
      "name": "Karl-Norbert Klotz"
    },
    {
      "affs": [
        1
      ],
      "name": "Elisabetta Coppi",
      "orcid": "0000-0003-4434-5919"
    },
    {
      "affs": [
        0
      ],
      "name": "Simone Adorinni",
      "orcid": "0000-0002-6888-7635"
    },
    {
      "affs": [
        2
      ],
      "name": "Stefano Moro",
      "orcid": "0000-0002-7514-3802"
    },
    {
      "affs": [
        1
      ],
      "name": "Anna Maria Pugliese"
    },
    {
      "affs": [
        0
      ],
      "name": "Stephanie Federico",
      "orcid": "0000-0003-2800-5287"
    },
    {
      "affs": [
        0
      ],
      "name": "Giampiero Spalluto",
      "orcid": "0000-0002-1957-7155"
    },
    {
      "affs": [
        0
      ],
      "name": "Tatiana Da Ros"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/56rwvx5y8mf59.bib",
  "cited_by": 0,
  "doi": "10.1002/cmdc.70528",
  "fulltext_url": "https://europepmc.org/articles/PMC13677798",
  "id": "56rwvx5y8mf59",
  "issns": [
    "1860-7179",
    "1860-7187"
  ],
  "landing_url": "https://europepmc.org/article/MED/42894265",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1314|Adenosine and Purinergic Signaling"
    ]
  ],
  "openalex": "W7222867591",
  "pdf_url": "https://europepmc.org/articles/PMC13677798?pdf=render",
  "pmcid": "PMC13677798",
  "pmid": "42894265",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/56rwvx5y8mf59.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:37Z",
      "native_id": "MED:42894265",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42894265"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1314|Adenosine and Purinergic Signaling",
      "subfield": "physiology"
    }
  ],
  "title": "Tuning the Triazolotriazine Scaffold Toward Selective A₃ Adenosine Receptor Antagonists: From Molecular Recognition to Neuroprotection.",
  "title_text": "Tuning the Triazolotriazine Scaffold Toward Selective A₃ Adenosine Receptor Antagonists: From Molecular Recognition to Neuroprotection.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:37Z",
  "url": "https://research.draconitic.com/paper/56rwvx5y8mf59",
  "venue": "ChemMedChem",
  "versions": []
}