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PHARMACOLOGICAL CHARACTERIZATION OF A PURINERGIC RECEPTOR (P2X7) ANTAGONIST IN‐VITRO AND IN‐VIVO
Author(s) -
Bhattacharya Anindya,
Maher Michael P,
Eckert William A,
Olafson Traci,
Wang Qi,
Ao Hong,
Wu Nyantsz,
Neff Robert,
Freedman Jamie M,
Lebsack Alec D,
Jones William M,
Hawryluk Natalie A,
Chaplan Sandra R,
Wickenden Alan D
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb460
Subject(s) - purinergic receptor , pharmacology , neuropathic pain , in vivo , ex vivo , antagonist , chemistry , receptor , in vitro , whole blood , medicine , biochemistry , biology , microbiology and biotechnology
Purinergic receptor subtype 7 (P2X7) is expressed on immune/glial cells and is hypothesized to modulate both inflammatory and neuropathic pain as seen by genetic disruption and pharmacological intervention. In this study, we report the characterization of a novel P2X7 receptor antagonist discovered by GlaxoSmithKline (compound 16; Chambers et al., 2009; RSC‐SCI Medicinal Chemistry Symposium, Cambridge, UK). The compound blocked human, rat and mouse recombinant P2X7 receptors with mean pIC 50 value of 6.8, 5.3 and 5.8 in FLIPR assay of intracellular calcium mobilization by Bz‐ATP. Compound 16 also attenuated Bz‐ATP dependent IL‐1β release in human and mouse whole blood with mean pIC 50 value of 6.2 and 5.5, respectively. The block induced by compound 16 was surmountable in human whole blood and it displaced [3H]‐A804598 in membrane preparations from human P2X7‐1321N1 cells. In whole‐cell patch clamp assay, 1 μM of the compound blocked 300 μM Bz‐ATP‐induced inward current in a reversible manner. The compound was orally bioavailable when dosed in mice and produced a dose dependent inhibition of IL‐1β at 2 hours post oral dose in a blood ex‐vivo assay (ED 50 ~ 1–3 mg/kg). At 15 mg/kg (oral) the compound also reversed mechanical allodynia in a mouse model of neuropathic pain (SNI). In addition, the compound also reversed CFA‐induced spontaneous inflammatory pain (weight bearing) in rats at 10 mg/kg tested at 1 and 2 hours post oral dose. Compound 16 is an efficacious P2X7 antagonist that maybe used as a tool to better understand the role of P2X7 in animal models of pain.