Development of a comprehensive set of P2 receptor pharmacological research compounds

Abstract

Pharmacological manipulation of P2X and P2Y receptors has been critical to the elucidation of the biological roles of these receptors within a multitude of physiological and pathological processes. Initial purinergic signalling research made use of compounds based on pyridoxal phosphate, suramin and nucleotide analogues; recently developed compounds are often derivatives of these early tools. Tocris Bioscience first entered the field of purinergic signalling reagents with the commercial release of the pyridoxal phosphate derivative, iso-PPADS. During the past two decades, Tocris has assembled a collection of over 50 compounds for P2 receptor modulation, including research tools commercialised from both academic and industrial laboratories. Recently, a number of P2X subtypeselective compounds have been generated by pharmaceutical company medicinal chemistry programmes, supplementing our range of P2Y-selective compounds. Here, we detail the current, commercially available agonists and antagonists of P2X 1,2/3,3,4,7 and P2Y 1,6,11,12 receptors; considered together, they form the foundations of a comprehensive P2 receptor pharmacological 'toolkit'.

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells

“…Specific pharmacological inhibitors of P2Y2R are not available so far, which precludes an investigation of its potential role in vivo in animal models for PKD. However, there is significant interest and success in developing compounds that specifically target P2 receptor subtypes [36]. Therefore, there is a good chance that selective P2Y2R inhibitors will be available in the future, and we propose that these should then be tested for their effect on cyst growth in vivo.…”

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

“…These include the assay (e.g., whether studying channel opening or pore formation), assay buffer (e.g., presence of divalent cations and bovine serum albumin can be inhibitory), host cell or cell type, agonist concentration, assay temperature, and antagonist mechanism of action (e.g., competitive or noncompetitive, reversible or irreversible, orthosteric or allosteric) (Hibell et al, 2001;Donnelly-Roberts and Jarvis, 2007). Of the antagonists listed in Table 2, PPADS, BBG, Reactive Blue, KN-62, and AZ10606120 are noncompetitive inhibitors of P2X7 (Jiang et al, 2000;Hibell et al, 2001;Honore et al, 2006;Felix et al, 2012). In contrast, A438079, A740003, and AZ11645373 are competitive inhibitors of P2X7 (Alcaraz et al, 2003;Nelson et al, 2006;Yan et al, 2011), whereas the mechanism of action of JNJ-47965567 remains to be determined.…”

Purinergic signalling in the enteric nervous system (An overview of current perspectives)

“…Thus P2Y1 receptors are blocked by MRS2179 (although MRS2279 and MRS2500 are more potent); on the other hand, P2Y2, P2Y6 and P2Y12 receptors are unaffected by either MRS2179 or MRS2279 (von Kügelgen, 2006;Felix et al, 2012). As a precautionary note, MRS2179 also blocks P2X1, although the antagonist is 10-fold less potent at P2X1 than at P2Y1 (Brown et al, 2000).…”

“…At this time, there was a limited range of pharmacological tools to identify P2X receptor subtypes and, accordingly, there remains doubt over the major P2X receptor subtypes present in the ENS based on pharmacological profiling. Progress has been made with highly-selective antagonists for a few key P2X subtypes (P2X1, P2X3, P2X2/3 and P2X7) (for evidential reviews, see: Felix et al, 2012;Ochoa-Cortes et al, 2014).…”