Contrary to published literature, none of the reported small molecule P2Y6 receptor antagonists exhibited functional activity in a Ca2+ mobilisation assay.
Reported small molecule P2Y6 receptor antagonists failed to show functional activity in a Ca2+ mobilisation assay, challenging previous literature and highlighting barriers in hP2Y6R pharmacology.
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 Ca 2+ 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.
Dane et al. (Sat,) reported a other. Reported small molecule P2Y6 receptor antagonists (compounds 1-4) vs. Vehicle/Control was evaluated on Inhibition of UDP-induced Ca2+ mobilisation. Contrary to published literature, none of the reported small molecule P2Y6 receptor antagonists exhibited functional activity in a Ca2+ mobilisation assay.