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. 2020 Jul;161(7):1425-1441.
doi: 10.1097/j.pain.0000000000001857.

Treatment of chronic neuropathic pain: purine receptor modulation

Kenneth A Jacobson  1 , Luigino Antonio Giancotti  2 , Filomena Lauro  2 , Fatma Mufti  2 , Daniela Salvemini  2
Affiliations

Treatment of chronic neuropathic pain: purine receptor modulation

Kenneth A Jacobson et al. Pain. 2020 Jul.

Abstract

Extracellular nucleosides and nucleotides have widespread functions in responding to physiological stress. The "purinome" encompasses 4 G-protein-coupled receptors (GPCRs) for adenosine, 8 GPCRs activated by nucleotides, 7 adenosine 5'-triphosphate-gated P2X ion channels, as well as the associated enzymes and transporters that regulate native agonist levels. Purinergic signaling modulators, such as receptor agonists and antagonists, have potential for treating chronic pain. Adenosine and its analogues potently suppress nociception in preclinical models by activating A1 and/or A3 adenosine receptors (ARs), but safely harnessing this pathway to clinically treat pain has not been achieved. Both A2AAR agonists and antagonists are efficacious in pain models. Highly selective A3AR agonists offer a novel approach to treat chronic pain. We have explored the structure activity relationship of nucleoside derivatives at this subtype using a computational structure-based approach. Novel A3AR agonists for pain control containing a bicyclic ring system (bicyclo [3.1.0] hexane) in place of ribose were designed and screened using an in vivo phenotypic model, which reflected both pharmacokinetic and pharmacodynamic parameters. High specificity (>10,000-fold selective for A3AR) was achieved with the aid of receptor homology models based on related GPCR structures. These A3AR agonists are well tolerated in vivo and highly efficacious in models of chronic neuropathic pain. Furthermore, signaling molecules acting at P2X3, P2X4, P2X7, and P2Y12Rs play critical roles in maladaptive pain neuroplasticity, and their antagonists reduce chronic or inflammatory pain, and, therefore, purine receptor modulation is a promising approach for future pain therapeutics. Structurally novel antagonists for these nucleotide receptors were discovered recently.

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Conflict of interest statement

Author Disclosure Statements:

Dr. Salvemini is founder of BioIntervene, Inc. a company developing A3AR agonists as analgesics for chronic pain. All other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Purinergic signaling pathways for purine nucleosides and nucleotides, and pyrimidine nucleotides. Extracellular ATP and other nucleotides originate from intracellular sources through cell damage, cotransmission, pannexin hemichannels, and other mechanisms. These nucleotides act on P2Y (GPCRs, activated by triphosphates, diphosphates and UDP-sugars) and P2X (ion channels, mainly by ATP) receptors. Ectonucleotidases (CD39, CD73) are largely responsible for the formation, from ATP, of adenosine that activates its four receptors. In general, adenosine receptor agonists and P2X/P2Y receptor antagonists induce pain relief in various models.
Figure 2.
Figure 2.
Structures of representative P2YR and P2XR antagonists that have been used in pain studies.
Figure 3.
Figure 3.
Structures of representative AR agonists that have been used in pain studies.
Figure 4.
Figure 4.
Structures of representative AR antagonists that have been used in pain studies.
Figure 5.
Figure 5.
Schematic representation of the molecular signaling pathways of A3AR agonists. Ca2+, calcium ions; ERK, extracellular signal-regulated kinase; GABA, gamma-aminobutyric Acid; GAD65, glutamic acid decarboxylase 65; GAT1, GABA transporter type 1; GLT-1, glutamate transporter 1; GS, glutamine synthetase; IL-1β, interleukin-1β; IL-4, interleukin-4; IL-10, interleukin-10; KCC2, potassium-chloride cotransporter protein; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; NF-kB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; NOS, nitric oxide synthase; p38, p38 mitogen-activated protein kinase; PN, peroxynitrite; RVM, rostral ventromedial medulla; TNFα, tumor necrosis factor alpha; SO, superoxide.
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