Purinergic Receptor Modulators and the Effect on Microglial Function.

Abstract

Purinergic receptors expressed on microglia are key modulators of neuroinflammation and neurodegeneration. Within the P2 subfamily, P2X4 and P2Y6 play essential roles in microgliamediated immune responses. Activation of P2X4 promotes release of pro-inflammatory cytokines, while P2Y6 induces microglial phagocytosis. As both pathways contribute to inflammatory pathogenesis, therapeutically targeting P2X4 and P2Y6 offers an exciting opportunity to advance our understanding of microglial function and address an unmet clinical need. Inhibition of P2X4 has emerged as a promising strategy for chronic pain and traumatic brain injury, yet current ligands often lack subtype selectivity and exhibit poor pharmacokinetic properties. Through incorporation of adamantane, this exploratory study sought to probe the binding domains of P2X4 and P2X7 and develop a predictive framework for selective purinergic antagonists. Although functional hP2X4R assays remain incomplete, in silico analysis of a diversified patent-derived compound library identified potential steric clashes between the adamantane substituent and the receptor environment, guiding future library design. Pharmacological inhibition of P2Y6 has demonstrated neuroprotective effects in in vivo acute amyloid pathology models, supporting its relevance in disorders such as Alzheimer’s disease. However, targeting P2Y6 therapeutically has been hindered by a lack of drug-like molecules. Structure–activity relationship studies aimed to define key pharmacophoric features for potent and selective P2Y6 antagonism, but diversification of reported antagonist 37 produced no novel leads and exposed inconsistencies in the literature, underscoring the need for robust, reproducible functional assays.