Author: Jacobsen, Anne-Marie ; Campbell, Brian ; Zorn, Stevin H ; Hestehave, Sara ; Zhou, Hua ; Gandhi, Adarsh ; Cajina, Manuel ; Poda, Suresh ; Hopper, Allen ; Munro, Gordon ; Chandresana, Gamini ; Segerdahl, Marta ; Staal, Roland G W ; Mӧller, Thomas

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.

01 Jul 2022·European Journal of PainQ2 · MEDICINE

P2X7 receptor‐mediated release of microglial prostanoids and miRNAs correlates with reversal of neuropathic hypersensitivity in rats

Q2 · MEDICINE

Article

Author: Munro, Gordon ; Staal, Roland ; Chandrasena, Gamini ; Cajina, Manuel ; Zhou, Hua ; Brodbeck, Robbin M. ; Schmidt, Megan ; Möller, Thomas ; Zorn, Stevin H. ; Segerdahl, Märta ; Gandhi, Adarsh ; Nattini, Megan E. ; Hestehave, Sara ; Khayrullina, Tanzilya ; Breysse, Nathalie ; Hopper, Allen T. ; Fallon, Shaun M. ; Christensen, Rie

AbstractBackgroundP2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 receptor signalling in pain, and the lack of a corresponding preclinical mechanistic biomarker.MethodsLu AF27139 is a highly selective and potent small molecule antagonist at rat, mouse and human forms of the P2X7 receptor, with excellent pharmacokinetic and CNS permeability properties. In the current experiments, we probed the utility of previously characterized and novel signalling cascades exposed to Lu AF27139 using cultured microglia combined with release assays. Subsequently, we assessed the biomarker potential of identified candidate molecules in the rat chronic constriction injury (CCI) model of neuropathic pain; study design limitations precluded their assessment in spared nerve injury (SNI) rats.ResultsLu AF27139 blocked several pain‐relevant pathways downstream of P2X7 receptors in vitro. At brain and spinal cord receptor occupancy levels capable of functionally blocking P2X7 receptors, it diminished neuropathic hypersensitivity in SNI rats, and less potently in CCI rats. Although tissue levels of numerous molecules previously linked to neuropathic pain and P2X7 receptor function (e.g. IL‐6, IL‐1β, cathepsin‐S, 2‐AG) were unaffected by CCI, Lu AF27139‐mediated regulation of spinal PGE2 and miRNA (e.g. rno‐miR‐93‐5p) levels increased by CCI aligned with its ability to diminish neuropathic hypersensitivity.ConclusionsWe have identified a pain‐relevant P2X7 receptor‐regulated mechanism in neuropathic rats, which could hold promise as a translatable biomarker and by association enhance the clinical progression of P2X7 receptor antagonists in neuropathic pain.SignificanceSub‐optimal translation of preclinical molecules has hindered the clinical development of novel mechanism of action analgesics. We have undertaken a comprehensive in vitro analysis of migroglial signalling mechanisms recruited upon P2X7 receptor activation, a number of which were shown to be modulated by a selective P2X7 receptor antagonist in a well characterized animal model of neuropathic pain. Subject to further confirmation in other neuropathic models, this opens up the possibility to investigate their clinical utility as potential pain biomarkers in patients.

22 Apr 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139

Q1 · MEDICINE

Article

Author: Thomsen, Christian ; Juhl, Martin ; Brodbeck, Robb ; Hopper, Allen T. ; Hornberg, Jorrit ; Dale, Elena ; Khayrullina, Tanzilya ; Grenon, Michel ; Thougaard, Annemette ; Zhang, Hong ; Gandhi, Adarsh ; Staal, Roland ; Kilburn, John Paul ; Möller, Thomas ; Jones, Ken ; Badolo, Lassina ; Menon, Veena ; Chandrasena, Gamini ; Zorn, Stevin H. ; Smagin, Gennady ; Poda, Suresh Babu ; Calice, Londye ; Nattini, Megan E. ; Cajina, Manuel ; Song, Dekun

There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability. In vivo mouse CNS microdialysis studies of lipopolysaccharide (LPS)-primed and 2'(3')-O-(benzoylbenzoyl)adenosine-5'-triphosphate (BzATP)-induced IL-1β release demonstrate functional CNS target engagement. Importantly, Lu AF27139 was without effect in standard in vitro and in vivo toxicity studies. Based on these properties, we believe Lu AF27139 will be a valuable tool for probing the role of the P2X7 receptor in rodent models of CNS diseases.

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Indication	Highest Phase	Country/Location	Organization	Date
Central Nervous System Diseases	Preclinical	US	Lundbeck Research USA, Inc.	-

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