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Peer-reviewedCC BYMedicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents

Investigation of reported small molecule P2Y6 receptor antagonists.

  • Chianna Dane1
  • André D J McKenzie1
  • Andrew P Montgomery1
  • Jonathan Du2
  • Eryn L Werry1
  • Michael Kassiou3
  1. 1School of Chemistry, Faculty of Science, University of Sydney, Sydney, NSW, 2006, Australia.
  2. 2Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
  3. 3School of Chemistry, Faculty of Science, University of Sydney, Sydney, NSW, 2006, Australia. [email protected].
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Abstract

Interest in the P2Y6 receptor (P2Y6R) has increased substantially over the past decade, driven by evidence that pharmacological inhibition is beneficial in neurodegenerative disease models, inflammatory pathologies, and cancer. However, therapeutic targeting of the P2Y6R has remained a challenge due to a lack of available drug-like molecules. In 2023 and 2024, benzimidazole and quinoline chemotypes respectively, were reported as potent P2Y6R antagonists with pharmacological relevance in an inflammatory bowel disease model. In the present study positive and negative controls from each chemotype were selected, and their functional activity at hP2Y6R was assessed prior to chemical diversification. Contrary to the published literature, none of the antagonists exhibited functional activity in our Ca²⁺ mobilisation assay reported herein. These findings emphasise the ongoing challenges in reliably assessing pharmacological activity at the hP2Y6R and highlight a key barrier to progression of the field.

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Cite

BibTeXRIS
BibTeX
@article{dane2026investigation,
  title = {{Investigation of reported small molecule P2Y6 receptor antagonists.}},
  author = {Chianna Dane and André D J McKenzie and Andrew P Montgomery and Jonathan Du and Eryn L Werry and Michael Kassiou},
  journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
  year = {2026},
  month = jul,
  doi = {10.1007/s00044-026-03591-w},
  url = {https://europepmc.org/article/MED/42873229},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Investigation of reported small molecule P2Y6 receptor antagonists.
AU  - Chianna Dane
AU  - André D J McKenzie
AU  - Andrew P Montgomery
AU  - Jonathan Du
AU  - Eryn L Werry
AU  - Michael Kassiou
PY  - 2026
DA  - 2026/07/11
JO  - Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents
DO  - 10.1007/s00044-026-03591-w
UR  - https://europepmc.org/article/MED/42873229
AB  - Interest in the P2Y6 receptor (P2Y6R) has increased substantially over the past decade, driven by evidence that pharmacological inhibition is beneficial in neurodegenerative disease models, inflammatory pathologies, and cancer. However, therapeutic targeting of the P2Y6R has remained a challenge due to a lack of available drug-like molecules. In 2023 and 2024, benzimidazole and quinoline chemotypes respectively, were reported as potent P2Y6R antagonists with pharmacological relevance in an inflammatory bowel disease model. In the present study positive and negative controls from each chemotype were selected, and their functional activity at hP2Y6R was assessed prior to chemical diversification. Contrary to the published literature, none of the antagonists exhibited functional activity in our Ca²⁺ mobilisation assay reported herein. These findings emphasise the ongoing challenges in reliably assessing pharmacological activity at the hP2Y6R and highlight a key barrier to progression of the field.
SN  - 1054-2523
SN  - 1554-8120
ER  -