Selective P2X7 receptor antagonists for chronic inflammation and pain |
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Authors: | William A Carroll Diana Donnelly-Roberts Michael F Jarvis |
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Institution: | (1) Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, R47W, AP10, 100 Abbott Park Road, Abbott Park, IL 60064–6101, USA |
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Abstract: | ATP, acting on P2X7 receptors, stimulates changes in intracellular calcium concentrations, maturation, and release of interleukin-1β (IL-1β), and following prolonged agonist exposure, cell death. The functional effects of P2X7 receptor activation facilitate several proinflammatory processes associated with arthritis. Within the nervous system, these proinflammatory processes may also contribute to the development and maintenance of chronic pain. Emerging data from genetic knockout studies have indicated specific roles for P2X7 receptors in inflammatory and neuropathic pain states. The discovery of multiple distinct chemical series of potent and highly selective P2X7 receptor antagonists have enhanced our understanding of P2X7 receptor pharmacology and the diverse array of P2X7 receptor signaling mechanisms. These antagonists have provided mechanistic insight into the role(s) P2X7 receptors play under pathophysiological conditions. In this review, we integrate the recent discoveries of novel P2X7 receptor-selective antagonists with a brief update on P2X7 receptor pharmacology and its therapeutic potential. |
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Keywords: | Calcium flux Pore formation Pain Inflammation Interleukin-1 Nerve injury Microglia Hyperalgesia Neural-glial interactions |
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