The P2X7 receptor provides the licensing signal for one of the strongest inflammatory responses in the body—assembly of the NLRP3 inflammasome.1,2 P2X7 receptor signaling is dysregulated in neurodegenerative pathologies, creating a constant and degradative pro-inflammatory environment, resulting in neuronal cell death.3 This neuronal cell death is the main cause of cognitive decline in neurodegenerative dementias, and both pharmacological blockade and ablation of the P2X7 receptor have ameliorated these conditions.4,5 The work herein will discuss the synthetic routes, challenges, and optimisations necessary to make small molecule P2X7 antagonists.
This work expands our current understanding of the structural requirements necessary for P2X7 receptor antagonism. We have underscored the necessity of both steric shape and size in directing binding poses whilst also highlighting the unique role adamantyl moieties play in P2X7 antagonism.
(1) Swanson, K. V.; Deng, M.; Ting, J. P.-Y. The NLRP3 Inflammasome: Molecular Activation and Regulation to Therapeutics. Nat Rev Immunol 2019, 19 (8), 477–489.
(2) Solini, A.; Rossi, C.; Santini, E.; Giuntini, M.; Raggi, F.; Parolini, F.; Biancalana, E.; Del Prete, E.; Bonuccelli, U.; Ceravolo, R. P2X7 Receptor/NLRP3 Inflammasome Complex and α-Synuclein in Peripheral Blood Mononuclear Cells: A Prospective Study in Neo-Diagnosed, Treatment-Naïve Parkinson’s Disease. European Journal of Neurology 2021, 28 (8), 2648–2656.
(3) Andrejew, R.; Oliveira-Giacomelli, Á.; Ribeiro, D. E.; Glaser, T.; Arnaud-Sampaio, V. F.; Lameu, C.; Ulrich, H. The P2X7 Receptor: Central Hub of Brain Diseases. Frontiers in Molecular Neuroscience 2020, 13 (7), 1–27.
(4) Illes, P. P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases. Int J Mol Sci 2020, 21 (17), 5996.
(5) Francistiová, L.; Bianchi, C.; Di Lauro, C.; Sebastián-Serrano, Á.; de Diego-García, L.; Kobolák, J.; Dinnyés, A.; Díaz-Hernández, M. The Role of P2X7 Receptor in Alzheimer’s Disease. Front. Mol. Neurosci. 2020, 13:94.