P2Y11 receptors are activated by ATP, P2Y12 and P2Y13 receptors prefer ADP and its analogs, and the P2Y14 receptor is preferentially activated by UDP-glucose (Abbracchio et al., 2009;
From: Advances in Pharmacology, 2011
Related terms:
Adenosine Diphosphate
Adenosine Triphosphate
Receptor Subtype
Purinergic P2Y Receptor
Purinergic P2Y1 Receptor
Purinergic P2Y12 Receptor
Purinergic P2Y2 Receptor
Purinergic P2Y6 Receptor
View all Topics
Pharmacology of Purine and Pyrimidine Receptors
Ivar von Kügelgen, T. Kendall Harden, in Advances in Pharmacology, 2011
F P2Y11 Receptor
A GPCR, the P2Y11 receptor, was cloned from a human placental library that exhibited 33% identity with the P2Y1 receptor and less than 30% identity with other P2Y receptors (Communi et al., 1997). Stable expression of this receptor conferred ATP-promoted activation of inositol lipid hydrolysis in 1321N1 human astrocytoma cells. However, in contrast to results with previously cloned P2Y receptors, activation of this receptor also resulted in activation of adenylyl cyclase albeit with lower efficiency than observed with activation of phospholipase C, i.e., higher concentrations of agonist were required (Communi et al., 1999; Qi et al., 2001a). The physiological significance of this bifurcation of signal has not been firmly established. This receptor is the only P2Y receptor identified to date that shows high selectivity for ATP—ADP is a weak agonist, and UTP and UDP are inactive. Interestingly, this GPCR is not present in the mouse or rat genome, and the canine P2Y11 receptor, which is 70% homologous to the human receptor, is more potently activated by ADP than ATP.
The P2Y11 receptor is expressed in human spleen, liver, intestine, brain, and pituitary (Abbracchio et al., 2006). It is also present in B lymphocytes and dendritic cells. The absence of this receptor in the mouse genome together with the facts that it is activated by ATP and no selective P2Y11 receptor probes are available has made resolution of the functions of this receptor very difficult. Potential roles in granulocyte differentiation and dendritic cell maturation and migration remain the best established functions for the P2Y11 receptor (Wilkin et al., 2001).
View chapterPurchase book
Pharmacology of Purine and Pyrimidine Receptors
Laszlo Köles, ... Peter Illes, in Advances in Pharmacology, 2011
2 Hetero-Oligomeric Assembly of P2Y Receptors
P2Y receptor subtypes may form heteromers with each other. Hetero-oligomerization between the P2Y1 and P2Y11 receptors which alters the ligand selectivity and is necessary for the subsequent internalization has recently been reported. It has also an important impact on P2Y11 receptor desensitization (Ecke et al., 2008). The dynamic architecture of P2Y4 and P2Y6 proteins involves the formation of complex hetero-oligomers as well. Such complexes comprise P2Y4 (dimeric) and P2Y6 (monomeric) receptors in native neuronal phenotypes. The monomeric/dimeric protomers are differently distributed in specialized membrane microdomains, and the homo- and hetero-oligomeric complexes are differently modulated by ligand activation (D'Ambrosi et al., 2007).
Hetero-oligomeric assembly of P2Y receptors with other G protein-coupled receptors has also been reported (for review, see Fischer & Krügel, 2007). For instance, A1 adenosine receptors interact with the P2Y1 or P2Y2 receptor, respectively. The A1–P2Y1 hetero-oligomer has P2Y1-like agonist selectivity but a preferential signaling pathway characteristic for the A1 receptors (Yoshioka et al., 2001). A functional cross talk between the P2Y1 and the A1 receptors involving their hetero-oligomerization was also confirmed in CNS synapses. P2Y1 receptor stimulation impaired the potency of A1 receptor-coupling to G protein, whereas the stimulation of A1 receptors increased the functional responsiveness of P2Y1 receptors (Tonazzini et al., 2007; Yoshioka et al., 2002).
The association of the A1 receptor with the P2Y2 receptor did not seem to affect the ligand selectivity of these receptors, and the stimulation of the P2Y2 receptor with UTP in the A1–P2Y2 receptor complex caused uncoupling of the A1 receptor from Gi proteins. On the contrary, the simultaneous activation of the two receptors enhanced signaling via Gq/11 protein, characteristic for P2Y2 activation (Suzuki et al., 2006). The homo- and hetero-oligomerization of the P2Y receptor subtypes with each other or with the adenosine receptors diversify the agonist and antagonist selectivity, signaling, and functional properties of the P2Y receptors and may explain some unexpected data obtained from experiments in native preparations. P2 proteins are considered not as separate entities but as dynamic and continuously changing and interacting cell constituents instead, and a combinatory calculation may allow the prediction of their complex dynamic architecture and sophisticated nature (Volonte et al., 2006).
A close colocalization of P2Y2 and β2 adrenergic receptors was also suggested in mouse pineal gland tumor cells indicating that a direct physical interaction/receptor heteromerization may exist not only among the members of the P2 receptor family but also between the purinergic and other G protein-coupled receptors (Suh et al., 2001). Further, P2Y4 receptors have been reported to be colocalized at the membrane level with NMDAR1 receptors. P2Y subunits are able to modulate the functions of various voltage- and/or ligand-gated ion channels, in a manner probably requiring localization of the receptor in close physical proximity to the channel (Cavaliere et al., 2004; Köles et al., 2008). Therefore, it cannot be excluded that metabotropic and ionotropic purinergic receptors may colocalize in higher-order complexes thereby further complicating the purinergic (patho)physiology and pharmacology.
View chapterPurchase book
Pharmacology of Purine and Pyrimidine Receptors
Eduardo R. Lazarowski, ... Silvia M. Kreda, in Advances in Pharmacology, 2011
A ATP Release from Resting Cells
The occurrence of basal ATP release was first suggested by studies indicating that resting levels of extracellular ATP conferred tonic activity to the P2Y2 and P2Y11 receptors endogenously expressed on Madin–Darby canine kidney (MDCK) cells. That is, resting MDCK cells exhibited basal inositol phosphate and cyclic AMP formation activities that were reduced by the addition of the nucleotidase apyrase or P2Y receptor antagonists (Ostrom et al., 2000). It was further established that steady-state levels of extracellular ATP on resting cells reflected a balance between rates of constitutive ATP release (calculated as 20–200 fmol/min per million cells) and ATP hydrolysis (Lazarowski et al., 2000). The physiological relevance of basal or constitutive ATP release may reside in determining the "set point" for P2Y/P2X receptor-mediated signaling (Corriden & Insel, 2010; Ostrom et al., 2000). Although constitutive ATP release may not suffice to promote P2Y/P2X receptor-mediated responses in many cells due to rapid hydrolysis, it provides a pathway for activation of adenosine receptors. For examples, in the airways, where adenosine is markedly more stable than ATP, constitutive release of ATP (and conversion to adenosine) confers tonic A2B receptor-promoted CFTR (cystic fibrosis transmembrane conductance regulator) Cl− channel activity that is crucial for ion/water transport in the airways (Huang et al., 2001; Lazarowski et al., 2004).
View chapterPurchase book
Purines and Purinoceptors: Molecular Biology Overview☆
G. Burnstock, in Reference Module in Biomedical Sciences, 2014
Second Messenger Systems and Ion Channels
P2Y1, P2Y2, P2Y4, and P2Y6 receptors couple to G-proteins to increase inositol trisphosphate (InsP3) and cytosolic calcium. Activation of the P2Y11 receptor by ATP leads to a rise in both cAMP and in InsP3, whereas activation by uridine 5′-triphosphate (UTP) produces calcium mobilization without InsP3 or cAMP increase. The P2Y13 receptor can simultaneously couple to G16, Gi, and, at high concentrations of ADP, Gs. The activation of several P2Y receptors is commonly associated with the stimulation of several mitogen-activated protein (MAP) kinases, in particular extracellular signal-regulated protein kinase-1/2.
In recent years, GPCRs in neurons and other excitable cells have been found to modulate the activity of voltage-gated ion channels in the cell membrane through certain actions of activated G-proteins. Such actions are now well established in closing (or, in certain cases, in opening or potentiating) various classes of K+ channels and voltage-gated Ca2 + channels. ATP (or UTP, or their products ADP or UDP) present at synapses, plus ATP diffusing from astrocytes, activates P2Y receptors on distinct subsets of brain neurons, regulating their activities by the coupling of those receptors to specific ion channels. While ion channel couplings of P2Y receptors are primarily of importance in neurons, they have in a few cases been detected also in various other tissues (e.g., in cardiac muscle cells). Among the channels with which the superior cervical ganglion cell membrane is well endowed are two types of voltage-gated channels, which are important in receptor-based regulation of neuronal activity, the Ca2 + channel of the N-type and the M-current K+ channel.
View chapterPurchase book
Retinal Glia
E.A. Newman, in Encyclopedia of Neuroscience, 2009
Neurotransmitter Receptors
Retinal Müller cells and astrocytes express a number of neurotransmitter and neuromodulator receptors. The most prominent among these are P2Y purinergic receptors. Amphibian Müller cells express P2Y1, P2Y2, P2Y6, and P2Y11 purinergic receptors. Müller cells of different species also express a number of glutamate receptors, including AMPA (GluR4), NMDA, and metabotropic types. GABAA, acetylcholine, dopamine, noradrenaline, adenosine (A2B), thrombin, and lysophosphatidic acid receptors as well as several neuroactive peptides receptors are expressed. Activation of many of these receptors evokes glial Ca2+ increases (see below). Interestingly, in the mammalian retina, glutamate is largely ineffective in evoking Ca2+ increases in Müller cells or astrocytes. In contrast, glutamate evokes large Ca2+ increases in astrocytes in brain slices and in culture. The insensitivity of retinal glial cells to glutamate may be a specialization to conditions in the retina, where glutamate is released continuously from neurons.
Receptors to a number of growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and nerve growth factor (NGF) are expressed. The effects of these factors are varied, and include the stimulation of DNA synthesis, mitosis, and cell proliferation, expression of cytoskeletal filaments, and the modulation of ion channels. EndothelinB receptors are expressed in Müller cells and are upregulated following retinal injury.
View chapterPurchase book
Purinergic Neurotransmission and Nucleotide Receptors
Geoffrey Burnstock, in Primer on the Autonomic Nervous System (Third Edition), 2012
P2Y Receptors
At present, there are eight accepted human P2Y receptors: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14 (see [16] and Table 18.1). The missing numbers represent either non-mammalian orthologs, or receptors having some sequence homology to P2Y receptors, but for which there is no functional evidence of responsiveness to nucleotides. In contrast to P2X receptors, P2Y receptor genes do not contain introns in the coding sequence, except for the P2Y11 receptor. Site-directed mutagenesis of the P2Y1 and P2Y2 receptors has shown that some positively charged residues in TM3, TM6 and TM7 are crucial for receptor activation by nucleotides. From a phylogenetic and structural (i.e., protein sequence) point of view, two distinct P2Y receptor subgroups characterized by a relatively high level of sequence divergence have been identified. The first subgroup includes P2Y1,2,4,6,11 and the second subgroup encompasses the P2Y12,13,14 subtypes. Selective antagonists have been identified for some P2Y receptor subtypes (see Table 18.1). P2Y1, P2Y2, P2Y4 and P2Y6 receptors couple to G proteins to increase inositol triphosphate (IP3) and cytosolic calcium. Activation of the P2Y11 receptor by ATP leads to a rise in both cAMP and in IP3, whereas activation by UTP produces calcium mobilization without IP3 or cAMP increase. The P2Y13 receptor can simultaneously couple to G16, Gi and, at high concentrations of ADP, to Gs. The activation of several P2Y receptors is commonly associated with the stimulation of several mitogen-activated protein kinases, in particular extracellular signal regulated protein kinase 1/2. In most species, ADP is a more potent agonist than ATP at P2Y1 receptors. Site-directed mutagenesis studies on the human P2Y1 receptor have shown that amino acid residues in TM3, TM6 and TM7 are critical determinants in the binding of ATP. P2Y2 receptors are fully activated by ATP and UTP, whereas ADP and UDP are much less effective agonists. Expression of P2Y2 receptor mRNA and protein has been detected in many peripheral tissues. UTP is the most potent activator of the recombinant human P2Y4 receptor. In human and mouse, P2Y4 mRNA and protein was most abundant in the intestine, but was also detected in other organs. The mouse, rat and human P2Y6 receptors are UDP receptors. A wide tissue distribution of P2Y6 mRNA and protein has been demonstrated, with the highest expression in spleen, intestine, liver, brain and pituitary. ATPγS is a more potent agonist at the P2Y11 receptor than ATP. ADP is the natural agonist of the P2Y12 receptor. It is heavily expressed in platelets where it is the molecular target of the active metabolite of the antiplatelet drug clopidogrel. The P2Y13 ADP-sensitive receptor is strongly expressed in the spleen, followed by placenta, liver, heart, bone marrow, monocytes, T-cells, lung and various brain regions. The P2Y14 receptor is activated by UDP, UDP-glucose as well as UDP-galactose, UDP-glucuronic acid and UDP-N-acetylglucosamine.
The formation of oligomers by P2Y receptors is likely to be widespread and to greatly increase the diversity of purinergic signaling. P2X receptors are often expressed in the same cells as P2Y receptors. Thus, there is the possibility of bi-directional cross-talk between these two families of nucleotide-sensitive receptors.
P2X receptors in general mediate fast neurotransmission, but are sometimes located prejunctionally to mediate increase in release of cotransmitters, for example glutamate in terminals of primary afferent neurons in the spinal cord. P2Y receptors are particularly involved in prejunctional inhibitory modulation of transmitter release, as well as cell proliferation. P2Y1,2,4,6 receptors have been described on subpopulations of sympathetic neurons, P2Y2 and P2Y4 receptors in intracardiac ganglia, P2Y1 and P2Y2 receptors on sensory neurons while P2Y1 receptors appear to be the dominant subtype on enteric neurons. P2Y2 (and/or P2Y4) receptors are expressed on enteric glial cells.
View chapterPurchase book
Extracellular Nucleotides and Renal Function
Matthew A. Bailey, ... Robert J. Unwin, in Seldin and Giebisch's The Kidney (Fourth Edition), 2008
P2Y Receptors
When a triphosphate chain is added to the 5′-carbon of the ribose moiety in adenosine (Fig. 1A), the resultant nucleotide (ATP) acts as a ligand for a distinct class of GPCRs called the P2Y receptors. There are eight recognized members of the mammalian P2Y subfamily: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14. These GPCRs were numbered in chronological order, according to their molecular isolation (21). Gaps appear in the sequence because they involve either P2Y receptors with no mammalian equivalent or P2Y-like sequences that were originally misidentified as nucleotide receptors. Thus, several nonmammalian proteins—skate P2Y, turkey P2Y, chick P2Y3 and Xenopus P2Y8—are not included in the list of mammalian P2Y receptors; while P2Y7 is a leukotriene B4 receptor, P2Y9 is a receptor for lysophosphatidic acid, and P2Y15 is a receptor for the citric acid cycle intermediates, α-ketoglutarate and succinate. Finally, P2Y5 and P2Y10 are orphan receptors with no defined ligand.
The P2Y receptor genes do not normally undergo alternative splicing. However, intergenic splicing occurs for the contiguous P2Y11 and SSF1 genes on chromosome 19p31, creating fusion proteins that function in the same way as the wild-type P2Y11 receptor (32). Additionally, a functional P2Y2 polymorphism has been reported for a mutation at a single codon (an arginine-cysteine transition) (78). Wild-type P2Y receptor proteins range in length from 328 residues (P2Y6 subtype) to 377 residues (P2Y2 subtype). The amino acid sequences of human P2Y receptor proteins are 19% to 55% identical but, where conservative substitutions are considered, these sequences show a 30% to 67% similarity. As noted previously, the P2Y receptor proteins have seven transmembrane spanning regions (TM1-7); the N-terminus projects into the extracellular space and the C-terminus is inside the cell. All the cloned P2Y receptors share the TM6 H-X-X-R/K motif, which is crucial for agonist activity (2). A fuller model of the docking sites for nucleotides—including the involvement of TM2, TM3, TM6, and TM7—has now been defined for the P2Y receptor family (33). Historically, ATP has been viewed as the natural agonist of native P2Y receptors but, from work on recombinant P2Y receptor proteins, it is now known that ATP subserves a range of roles, including agonist, partial agonist, and antagonist, or it may be inert. P2Y1, P2Y12, and P2Y13 receptors are activated principally by ADP where, in all probability, this nucleoside diphosphate arises from the enzymatic breakdown of extracellular ATP. At very high levels of P2Y receptor expression, ATP can also act as a partial agonist at P2Y1, P2Y12, and P2Y13 receptors. However, at low levels of P2Y receptor expression, ATP can revert to the role of an antagonist at these sites, indicating that its efficacy as an agonist is generally low and highly dependent on receptor reserve (81). The P2Y6 subtype is also activated by ADP, although more potently by UDP and weakly by ATP.
P2Y2 and P2Y11 receptors are activated fully by ATP and less potently by ADP. Both these subtypes are also activated by UTP, which, again, is less potent than ATP. In contrast, the human form of P2Y4 is activated primarily by UTP and, surprisingly, antagonized by ATP even at high receptor numbers. The mouse and rat isoforms of P2Y4 are fully activated by both UTP and ATP. Lastly, the P2Y14 receptor is potently activated by UDP-glucose (a sugar nucleotide) and completely unaffected by extracellular UTP, ATP, or glycosylated forms of adenine nucleotides. Thus, P2Y14 shows the most restricted agonist profile of all the accepted P2Y receptor subtypes.
There are very few ATP analogues that serve as wholly selective agonists for P2Y receptors (Table 1). The N-methanocarba-ADP derivative MRS 2365 is a very potent and selective agonist for P2Y1 receptors (29) and the βγ-meATP derivative AR-C67085 is a selective agonist for the P2Y11 receptor (32). The remainder of the P2Y subtypes are stimulated to varying degrees by 2-alkylthio derivatives (e.g. 2meSATP and 2meSADP), phosphorothioate derivatives (ATPγS and ADPβS or, in some cases, UTPγS and UDPβS), or symmetric and asymmetric dinucleotides (e.g., Ap4A, Up4U, and dCp4U). Thus, the pharmacological identification of P2Y receptor subtypes normally requires a cross-comparison of the activity of several nucleotides, to define the relative order of agonist potencies against the reference of ATP.
TABLE 1. Monomeric P2y Receptor Subtypes
P2Y1P2Y2P2Y4P2Y6P2Y11P2Y12P2Y13P2Y14Gene (human)3q25.211q13.5Xq1311q13.519p13.23q24-253q24-253q24-25Protein (human)372 aa376 aa365 aa328 aa371 aa342 aa333 aa338 aaNatural ligands (pEC50)ADP (8.6)ATP (7.1)UTP (7.6)ADP (4.5)ATP (5.5)ADP (7.4)ADP (8.0)UDP-glucose (7.1)ATP (6.5)UTP (7.7)ATP (6.o) (r,m*)UDP (7.0)UTP (5.2)ATP (6.2)ATP (6.6)Ap4A (6.2)Up4U (7.0)GTP (5.2)IDP (4.5)IDP (6.3)Other agonists (pEC50)2MeSATP (8.5)2MeSATP (4.6)2MeSATP (1o)2MeSATP (7.9)2MeSADP (8.7)2MeSADP (1o)2MeSADP (7.1)ATPγS (6.4)ATPγS (6.2)UTPγS (5.8)ATPγS (5.5)ADPβS (6.1)UDPβS (7.6)ADPβS (7.0)ADPβS (7.4)MRS 2365 (9.o)AR-C67o85 (5.8)Antagonist: selective (pIC50)MRS 2279 (7.3)MRS 2578 (7.5)AMPS (3.5)
2MeSAMP (5.9)
PPADS (3.7)
AR-C69931 (9.0)
PPADS (4.9)
AR-C69931 (8.3)
MRS 2179 (6.5)Antagonist: nonselective (pIC50)PPADS (5.4)PPADS (4.8)suramin (5.8)suramin (∼4.5)suramin (4.8)suramin (5.4)suramin (5.6)RB-2 (6.5) (c*)RB-2 (4.7) (r, m*)RB-2 (4.5)RB-2 (5.9)RB-2 (5.7)SignalingGq/11Gq/11Gq/11Gq/11Gq/11 and GSGi/oGi/oGi/oPLCβ activationPLCβ activationPLCβ activationPLCβ activationPLCβ and AC activationAC inhibitionAC inhibitionAC inhibition
Pharmacological and signaling properties of monomeric P2Y receptors, listing the natural and synthetic agonists, and the selective and nonselective antagonists for each subtype.
Data are given as –log10 EC50 (pEC50) and –log10 IC50 (pIC50). In some cases, data are given for chick (c*), mouse (m*) and rat (r*) isoforms; all other data are for humans. aa, amino acids.
The concentration range over which P2Y receptor agonists act is neither critically important nor necessarily defining of phenotype, because the absolute number of P2Y receptors in a cell will determine the position of the concentration/response curve. This phenomenon, based on the relationship between the receptor reserve and the G-protein pool in a cell, is a common analytical problem for all types of agonist-activated GPCRs (81).
P2Y receptor–selective antagonists also are few in number. For P2Y1, the bisphosphate ADP derivatives MRS2179 (2′-deoxy-N6-methyladenosine-3′,5′-bisphosphate) and MRS2279 (2-Chloro-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate) are effective and selective antagonists (73); and the P2Y6 subtype is antagonised by MRS2578 (1,4-di-[phenylthioureido] butane) (101). All members of the P2Y receptor family are nonselectively antagonized by high concentrations of suramin, PPADS (pyridoxal-5-phosphate-6-azophenyl 2′,4′-disulphonic acid), or reactive blue 2 (RB-2).
View chapterPurchase book
Pharmacology of Purine and Pyrimidine Receptors
Filip Kukulski, ... Jean Sévigny, in Advances in Pharmacology, 2011
I Introduction
Extracellular nucleotides via P2 receptors and extracellular adenosine via P1 receptors are involved in a number of physiological processes (Abbracchio & Burnstock, 1998; Abbracchio et al., 2009; Di Virgilio et al., 2009; Hasko et al., 2008). The presence of nucleotides in the extracellular space not only arises as a result of cellular damage but also occurs in a controlled fashion by their secretion from activated cells (reviewed in Chapter 8). The information encrypted in nucleotide release is delivered into the cells through plasma membrane-bound ionotropic P2X (P2X1–7) and metabotropic P2Y (P2Y1,2,4,6,11–14) receptors. P2 receptor subtypes differ in respect to their selectivity toward nucleotides and are coupled to different intracellular signaling pathways. All P2X and P2Y11 receptors are activated by ATP; P2Y2 by ATP and UTP; P2Y1, P2Y12, and P2Y13 by ADP; P2Y4 by UTP; P2Y6 by UDP (and UTP in mouse; Kauffenstein et al., 2010a); and P2Y14 by UDP-glucose (Abbracchio et al., 2006). In addition, nucleotides can also activate other G protein-coupled receptors such as cysteinyl leukotriene receptor-1 and -2 (CysLT1R and CysLT2R), and GPR17 (Ciana et al., 2006; Mamedova et al., 2005; von Kugelgen, 2006).
Extracellular adenosine originates either from the catabolism of nucleotides by ectonucleotidases or from transport through SLC29 transporter formerly known as equilibrative nucleoside transporters (ENT; Colgan et al., 2006; Conde & Monteiro, 2004; Parkinson et al., 2005; Sowa et al., 2009; Zylka et al., 2008). Once outside the cell, adenosine activates G protein-coupled P1 receptors (A1, A2A, A2B, and A3) that exert physiological responses (Jacobson & Gao, 2006) often opposite to those activated by extracellular nucleotides through P2 receptors.
The activation of P2 and P1 receptors is regulated by ectoenzymes that either eliminate or produce extracellular nucleotides and adenosine. This review presents these enzymes and recent development about their described functions in three systems of our interest: inflammation, vascular tone, and neurotransmission. In addition, recent progress in the development of specific inhibitors for some of these enzymes is also presented.
View chapterPurchase book
Cancer, Immunology and Inflammation, and Infectious Disease
J.L. Adams, ... J. Yang, in Comprehensive Medicinal Chemistry III, 2017
5.11.4.2.1 P2X and P2Y receptor modulators
There are seven subtypes of P2X ion channel receptors (P2X1–7) and eight subtypes of G protein-coupled P2Y receptors, many of which are expressed on immune cells in the TME. Elevated eATP can activate the P2 receptors on DCs to enhance specific CD8+ T cell cytotoxicity.87 Activation of P2X7R is believed to be an important proinflammatory pathway to stimulate the immune response. If so, a P2X7R agonist or an inhibitor of ATP degradation would boost the antitumor immunity. However, in human tumors overexpression of P2X7R is better correlated with promoting tumor growth and progression.93 Conversely, P2X7R-deficient mice demonstrate accelerated tumor growth and metastatic spreading.94 Thus the potential impact of a P2X7R agonist on tumor growth remains unclear. The effect of ATP on P2Y11 receptors present on DCs is to change the cytokine profile toward Th2 immunity and in doing so favor immunosuppressive rather than immunostimulatory pathways.95
Potent antagonists of P2X7 have been described, exemplified (Fig. 12) by the bio-isosteric compounds dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one 29 (hP2X7 IC50 = 0.7 nM)96 and 6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine 30 (hP2X7 IC50 = 4.2 nM)97 which demonstrate low-nanomolar antagonism in Ca2 + efflux FLIPR assays. Since the majority of researchers have been pursuing mood disorders, the focus has been on improving the CNS-penetration of these antagonists. A detailed exploration of the structural determinants for P2X receptor binding has been published by Dal Ben et al.98 providing insight into the variations between the P2X 1–7 receptors, the differences between human and rat P2X receptors (important for the interpretation of rat models of CNS disorders) and progress toward the synthesis of subtype selective receptor compounds.

Sign in to download full-size image
Fig. 12. P2X7 antagonists.
Similarly, detailed reviews of P2Y receptor agonists and antagonists by Jacobson et al.99 highlight the breadth of research into nucleoside and non nucleoside modulators of this large class of GPCRs. For example, structural modifications within an adenosine template can result in conversion of a potent and selective pyrophosphate-based P2Y1 agonist MRS2365 (31; P2Y1 pEC50 = 9.4) into a potent and selective diphosphate-based antagonist MRS2500 (32; P2Y1 pIC50 = 9.0) (Fig. 13).100

Sign in to download full-size image
Fig. 13. Conversion of potent P2Y1 agonist into potent and selective P2Y1 antagonist.
The successful synthesis of both selective agonists and antagonists for those P2 receptor subtypes provides hope that this may prove true for the entire receptor family. As such, we may soon have the tools to discern which P2 receptors may have therapeutic utility to boost the immune response to cancer.