Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X(7) receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
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http://dx.doi.org/10.1016/j.bmcl.2011.04.034 | DOI Listing |
Sci Adv
January 2025
Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
P2X receptors (P2XRs) are adenosine 5'-triphosphate (ATP)-gated ion channels comprising homomeric and heteromeric trimers of seven subtypes (P2X1-P2X7) that confer different rates of desensitization. The helical recoil model of P2XR desensitization proposes stability of the cytoplasmic cap sets the rate of desensitization, but timing of its formation is unclear for slow-desensitizing P2XRs. We report cryo-electron microscopy structures of full-length wild-type human P2X4 receptor in apo closed, antagonist-bound inhibited, and ATP-bound desensitized states.
View Article and Find Full Text PDFACS Pharmacol Transl Sci
January 2025
Pharmaceutical Institute, Pharmacology and Toxicology, University of Bonn, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany.
Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors.
View Article and Find Full Text PDFNeurochem Res
January 2025
Department of Biochemistry and Molecular Biology, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil.
Purinergic signaling plays a major role in aging and neurodegenerative diseases, which are associated with memory decline. Blackcurrant (BC), an anthocyanin-rich berry, is renowned for its antioxidant and neuroprotective activities. However, evidence on the effects of BC on purinergic signaling is lacking.
View Article and Find Full Text PDFBurns
December 2024
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11, Mandalay Road, 308232, Singapore; Skin Research Institute Singapore, Level 17, Clinical Sciences Building, 11, Mandalay Road, 308232, Singapore; National Skin Centre Singapore, 1 Mandalay Rd, 308205, Singapore. Electronic address:
Burns are dynamic injuries characterized by an initial zone of necrosis that progresses to compromise surrounding tissue. Acute inflammation and cell death are two main factors contributing to burn progression. These processes are modulated by Connexin43 (Cx43) hemichannels and gap junctions in burns and chronic wounds.
View Article and Find Full Text PDFSci Rep
January 2025
Department of Neurosurgery and Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Although low-intensity focused ultrasound (LiFUS) with microbubbles is used to temporally open the blood-brain barrier (BBB), the underlying mechanism is not fully understood. This study aimed to analyze BBB-related alterations in the brain microenvironment after LiFUS, with a focus on the involvement of the purinergic P × receptor. Sprague-Dawley rats were sonicated with LiFUS at 0.
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