In the CNS, the ATP-gated ion channel P2X7 is expressed in glial cells and modulate neurophysiology via release of gliotransmitters including the pro-inflammatory cytokine, IL-1β. In this study we have characterized JNJ-42253432 as a centrally permeable (brain to plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in-vivo testing in rodents. JNJ-42253432 is a high affinity antagonist for rat (pKi 9.1 ± 0.07) and human (pKi 7.9 ± 0.08) P2X7 channel. The compound blocked the ATP-induced current and Bz-ATP induced release of IL-1β in a concentration dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1β induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of serotonin transporter (SERT) resulting in an ED50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced EEG spectral power in the alpha-1 band in a dose dependent manner; the compound also attenuated amphetamine induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by footshock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study we characterize JNJ-42253432 as a novel, brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.
- The American Society for Pharmacology and Experimental Therapeutics