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Pharmacotherapy of Neurochemical Imbalances
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar, Suvarna Ingale
ATP has now also established its role as a transmitter through its widespread receptor-mediated actions in the body. ATP binds with two types of receptors, P2X and P2Y receptors. P2X receptors are ligand-gated ion channel receptors subdivided into seven subtypes (P2X1 to P2X7). P2X receptors are widely distributed all over the body. P2X1 and P2X2 receptors are found in the dorsal horn, and hence play an important role in sensory transmission. P2Y receptors are GPCRs and there are eight subtypes of P2Y receptors such as P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14 (Rang et al., 2011; Edward and Gibb, 1993; Barrett et al., 2009; Webster, 2001).
P2X receptor antagonists and their potential as therapeutics: a patent review (2010–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Chianna Dane, Leanne Stokes, William T Jorgensen
Expression of P2X receptors is diverse accounting for their multifarious roles, including inflammation, neurodegenerative diseases, autocrine feedback loops, and neuropathic pain [8,9]. Consequently, P2X receptors have been recognized as prospective therapeutic targets for a variety of disorders, including chronic neuropathic and inflammatory pain (P2X3, P2X2/3, P2X4, P2X7), dysfunctional urinary bladder (P2X1, P2X3, P2X2/3), cancer (P2X7), and thrombosis (P2X1) [10,11]. Considerable advancement in understanding the pharmacological significance of the P2X receptors has been made through the development and in vivo evaluation of potent, subtype-selective antagonists [11]. In this review, we will discuss the representative structures and pharmacological data of known antagonists of the P2X receptors with the focus on recently patented compounds.
P2X1: a unique platelet receptor with a key role in thromboinflammation
Published in Platelets, 2021
ATP, the endogenous ligand of P2X1 ion channels, is released from platelet-dense granules during their activation. It is also released by activated endothelial cells and leukocytes as well as, passively, by dead cells upon tissue injury [14]. ATP reaches high concentration at sites of inflammation, where it acts as a key damage-associated molecular pattern (DAMP) [15]. ATP-induced P2 receptor signaling on immune cells participates in early inflammatory and immune responses [16]. ATP induces NLRP3 inflammasome formation through binding to P2X7 ion channel on monocytes [17]. Neutrophil chemotaxis depends on ATP-mediated activation of P2Y2 receptors [18]. ATP also contributes to the resolution of inflammation. Indeed, ATP released by dying cells attracts macrophages to the site of damage, which promotes clearance of dead cells [19]. ATP signaling is tightly regulated through the action of the ATP hydrolyzing enzyme ecto-nucleoside triphosphate diphosphohydrolase CD39 [20].
Ion channels and ion homeostasis in the platelet and megakaryocyte
Published in Platelets, 2021
Kirk A. Taylor, Martyn P. Mahaut-Smith
Platelets are known to contribute to a number of physiological processes beyond hemostasis, such as angiogenesis and immunity. Consequently they are also potential therapeutic targets for prevention of disease states beyond thrombosis, such as sepsis, cancer and stroke. This is a particular focus of the review by Oury and Wera [15] which considers the evidence for a unique role of platelet P2X1 nonselective cation channels in thromboinflammation. Substantial amounts of ATP, the physiological ligand for P2X1 channels, are released at sites of injury and inflammation and also secreted by activated platelets from their dense granules. The contribution of this nucleotide to platelet activation is often overshadowed by the central importance of co-secreted ADP which stimulates P2Y G-protein-coupled receptors. The review by Taylor and colleagues [12] is of relevance to this topic as the large pore pannexin-1 channels and connexin hemichannels proteins represent non-vesicular pathways for the release of cytosolic ATP and potentially also ADP.