AK1780, a selective P2X7 receptor antagonist with high central nervous system penetration, exhibits analgesic effect in rat neuropathic pain model.

It is widely recognized that the mechanisms underlying neuropathic pain are complicated, and no existing analgesics give sufficient effects to all patients suffering it, as such there remains a high unmet medical need for well tolerated analgesics. The P2X7 receptor (P2X7R), an adenosine triphosphate-activated ion-gated channel, is an attractive therapeutic target for neuropathic pain according to previous in vitro and in vivo studies. Here, we introduce a novel P2X7R inhibitor, AK1780 (LY3857210). AK1780 inhibited calcium influx in human or rat P2X7R expressing cells with IC of 19 or 8.4 nmol/L, respectively, while AK1780 did not show activity against other P2X family as well as a non-binding profile for 133 other targets. Furthermore, AK1780 suppressed IL-1β secretion from rat primary microglial cells which may play an important role in pain sensation. AK1780 attenuated paw withdrawal threshold after 2 mg/kg oral administration, in which both plasma and CSF concentrations achieved in vitro IC, determined by calcium influx assay, with no apparent CNS side effects. More interestingly, the receptor occupancy in the brain was correlated with analgesic effects in rats. These data suggest that blockade of P2X7R with AK1780 in the CNS can have analgesic properties without any CNS adverse effects. PERSPECTIVE: This article presents in vitro and in vivo data for AK1780 (LY3857210), a selective P2X7R antagonist. The data reasonably explain its analgesic effect in the view of PK/PD, indicating that AK1780 may potentially suppress neuropathic pain without any CNS adverse effects.