Tuning the Triazolotriazine Scaffold Toward Selective A₃ Adenosine Receptor Antagonists: From Molecular Recognition to Neuroprotection.
5 affiliations
- 1Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy.
- 2Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
- 3Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
- 4Rudolf-Virchow-Zentrum - Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
- 5Institut für Pharmakologie und Toxikologie, University of Würzburg, Würzburg, Germany.
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.
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BibTeX
@article{kost2026tuning,
title = {{Tuning the Triazolotriazine Scaffold Toward Selective A₃ Adenosine Receptor Antagonists: From Molecular Recognition to Neuroprotection.}},
author = {Veronika Kost and Filippo Prencipe and Federica Panozzi and Veronica Salmaso and Sonja Kachler and Karl-Norbert Klotz and Elisabetta Coppi and Simone Adorinni and Stefano Moro and Anna Maria Pugliese and Stephanie Federico and Giampiero Spalluto and Tatiana Da Ros},
journal = {ChemMedChem},
year = {2026},
month = oct,
doi = {10.1002/cmdc.70528},
url = {https://europepmc.org/article/MED/42894265},
note = {CC BY},
}
RIS
TY - JOUR
TI - Tuning the Triazolotriazine Scaffold Toward Selective A₃ Adenosine Receptor Antagonists: From Molecular Recognition to Neuroprotection.
AU - Veronika Kost
AU - Filippo Prencipe
AU - Federica Panozzi
AU - Veronica Salmaso
AU - Sonja Kachler
AU - Karl-Norbert Klotz
AU - Elisabetta Coppi
AU - Simone Adorinni
AU - Stefano Moro
AU - Anna Maria Pugliese
AU - Stephanie Federico
AU - Giampiero Spalluto
AU - Tatiana Da Ros
PY - 2026
DA - 2026/10/01
JO - ChemMedChem
DO - 10.1002/cmdc.70528
UR - https://europepmc.org/article/MED/42894265
AB - 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.
SN - 1860-7179
SN - 1860-7187
ER -