RT Journal Article
SR Electronic
T1 Pharmacology of a novel CNS penetrant P2X7 antagonist JNJ-42253432
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.114.218487
DO 10.1124/jpet.114.218487
A1 Brian Lord
A1 Leah Aluisio
A1 James R Shoblock
A1 Robert Neff
A1 Elena I Varlinskaya
A1 Marc Ceusters
A1 Timothy W Lovenberg
A1 Nicholas Carruthers
A1 Pascal Bonaventure
A1 Michael A Letavic
A1 Terrence Deak
A1 Wilhelmus Drinkenburg
A1 Anindya Bhattacharya
YR 2014
UL http://jpet.aspetjournals.org/content/early/2014/09/30/jpet.114.218487.abstract
AB 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.