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Guided by previous structure\u2013activity relationship studies, the C2\u2010furyl substituent was replaced with phenyl or 4\u2010methoxyphenyl moieties to improve A\n                    <jats:sub>3<\/jats:sub>\n                    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 A\n                    <jats:sub>3<\/jats:sub>\n                    AR affinity, yielding compound\n                    <jats:bold>15<\/jats:bold>\n                    as the most potent antagonist of the series (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    \u2009=\u20090.485\u2009nM), whereas incorporation of a 4\u2010methoxyphenyl group at C2 substantially improved subtype selectivity, exemplified by compound\n                    <jats:bold>30<\/jats:bold>\n                    (&gt;2800\u2010fold selective for A\n                    <jats:sub>3<\/jats:sub>\n                    AR). Molecular docking at the recently determined antagonist\u2010bound structure of the A\n                    <jats:sub>3<\/jats:sub>\n                    AR rationalized these trends and identified key structural determinants of A\n                    <jats:sub>3<\/jats:sub>\n                    AR preference. The biological relevance of A\n                    <jats:sub>3<\/jats:sub>\n                    AR blockade was investigated in rat hippocampal slices subjected to oxygen\u2010glucose deprivation. Compound\n                    <jats:bold>15<\/jats:bold>\n                    delayed anoxic depolarization and, when administered during ischemia, prevented its onset in most slices and promoted near\u2010complete recovery of synaptic transmission. These findings identify TT derivatives as promising and highly selective A\n                    <jats:sub>3<\/jats:sub>\n                    AR antagonists with potential neuroprotective applications in cerebral ischemia.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70528","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:28:11Z","timestamp":1792380491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tuning the Triazolotriazine Scaffold Toward Selective A\n                    <sub>3<\/sub>\n                    Adenosine Receptor Antagonists: From Molecular Recognition to Neuroprotection"],"prefix":"10.1002","volume":"21","author":[{"given":"Veronika","family":"Kost","sequence":"first","affiliation":[{"name":"Department of Chemical and Pharmaceutical Sciences University of Trieste  Trieste 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