Neuroinflammation is an adaptive response of the central nervous system (CNS) to diverse potentially harmful stimuli, closely associated with neurodegeneration and typically characterized by the activation of microglia and astrocytes. Efficiency of the inflammatory response is due to its rapidity of setting but also on its transiency. A non-resolved acute inflammatory response can lead to chronic CNS inflammation and neurodegeneration. Therefore, the resolution of inflammation is considered a valid therapeutic approach for chronic inflammation and its related diseases. The purinergic P2X7R (P2X7R), a non-selective cation channel expressed in the immune system and central nervous systems, is emerging as a gatekeeper of inflammation promoting inflammasome formation and the release of proinflammatory cytokines and chemokines. Recently, we have developed a new class of active non-competitive P2X7R antagonists having 2-chlorobenzamide scaffold, a core present in many potent compounds. To fulfill the characteristics of a brain penetrant compound the design of the new P2X7R antagonists has been filtered by applying the CNS-MultiParameterOptimization (CNS-MPO), an algorithm tracking the six physicochemical properties that are pivotal for successful CNS ligands, and assisted by molecular docking using the currently available 3D structures of P2X7R present in the Protein Data Bank database. The target compounds have been synthesized, characterized and tested for their ability to block agonist-induced increase of intracellular calcium in HEK-293 cells stably expressing human or rat P2X7 receptors. Here we analyze the structure-activity relationships of the developed compounds and speculate on the possibility to develop novel PET and SPECT radiotracers.
FIGHTING CHRONIC NEUROINFLAMMATION WITH NOVEL P2X7 RECEPTOR ANTAGONISTS: AN INTRIGUING THERAPEUTIC APPROACH TO THE NEURODEGENERATIVE DISEASES
Ghafir El Idrissi, I.;Lacivita, E.;Leopoldo, M.
2024-01-01
Abstract
Neuroinflammation is an adaptive response of the central nervous system (CNS) to diverse potentially harmful stimuli, closely associated with neurodegeneration and typically characterized by the activation of microglia and astrocytes. Efficiency of the inflammatory response is due to its rapidity of setting but also on its transiency. A non-resolved acute inflammatory response can lead to chronic CNS inflammation and neurodegeneration. Therefore, the resolution of inflammation is considered a valid therapeutic approach for chronic inflammation and its related diseases. The purinergic P2X7R (P2X7R), a non-selective cation channel expressed in the immune system and central nervous systems, is emerging as a gatekeeper of inflammation promoting inflammasome formation and the release of proinflammatory cytokines and chemokines. Recently, we have developed a new class of active non-competitive P2X7R antagonists having 2-chlorobenzamide scaffold, a core present in many potent compounds. To fulfill the characteristics of a brain penetrant compound the design of the new P2X7R antagonists has been filtered by applying the CNS-MultiParameterOptimization (CNS-MPO), an algorithm tracking the six physicochemical properties that are pivotal for successful CNS ligands, and assisted by molecular docking using the currently available 3D structures of P2X7R present in the Protein Data Bank database. The target compounds have been synthesized, characterized and tested for their ability to block agonist-induced increase of intracellular calcium in HEK-293 cells stably expressing human or rat P2X7 receptors. Here we analyze the structure-activity relationships of the developed compounds and speculate on the possibility to develop novel PET and SPECT radiotracers.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
