Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Abstract

In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1b. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] 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 the rat (pK i 9.1 6 0.07) and human (pK i 7.9 6 0.08) P2X7 channel. The compound blocked the ATPinduced current and Bz-ATP [29(39)-O-(4-benzoylbenzoyl)adenosine-59-triphosphate tri(triethylammonium)]-induced release of IL-1b in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED 50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1b 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 the serotonin transporter (SERT) resulting in an ED 50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the a-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 foot-shock. 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.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…To study the manic pole of bipolar disorder, genetic deficiency and pharmacological blockade of P2X7 receptors attenuated hyperactivity induced by amphetamine in all studies examined (Bhattacharya et al, 2013;Csolle et al, 2013a;Gubert et al, 2014;Lord et al, 2014). These findings indicate that the presence and endogenous activation of P2X7 receptors contributes to behavioral changes induced by either negative or positive challenges, and the blockade of the receptor alleviates these fluctuations.…”

“…While JNJ-42253432, a novel brain-penetrant P2X7 receptor antagonist, did not affect footshock induced decreases in social interactions, it elicited a robust increase in overall social activity (Lord et al, 2014). Therefore, P2X7 receptor modulation may represent an intriguing possibility for interfering with neuropsychiatric conditions characterized by social deficit (e.g.…”

Preclinical Evaluation of a P2X7 Receptor–Selective Radiotracer: PET Studies in a Rat Model with Local Overexpression of the Human P2X7 Receptor and in Nonhuman Primates

“…Reduced uptake of 11 C-JNJ-54173717 was observed after pretreatment (2.5 mg/kg intravenously, 10 min before tracer injection) with cold JNJ-54173717 and with JNJ-42253432 (Fig. 5) (15). The plasma SUVs of intact 11 C-JNJ-54173717 for the first baseline scan were 0.55, 0.33, and 0.24, and for pretreatment (with JNJ-54173717) they were 0.52, 0.34, and 0.25 at 10, 30, and 60 min after tracer injection, respectively.…”

“…For the self-block experiment, the authentic reference JNJ54173717 was dissolved in a vehicle containing 20% (2-hydroxypropyl)-b-cyclodextrine and 2 equivalents HCl. In a second pretreatment experiment, JNJ-42253432 (a central nervous system-penetrant P2X7R antagonist and structurally unrelated compound (15)) was dissolved in a vehicle containing 20% (2-hydroxypropyl)-b-cyclodextrine and 0.75 equivalents HCl (no vehicle was injected in the baseline scan). These formulations were injected intravenously 10 min before tracer injection at a dose of 2.5 mg/kg.…”

“…In addition, several animal models for neurodegenerative disorders such as Alzheimer's disease and Huntington's disease (9)(10)(11) showed that proinflammatory cytokines correlated with upregulated P2X7R expression and increased adenosine triphosphate sensitivity, putting forward P2X7R as a valuable alternative marker for microglial activation and inflammation (8,12). In a recent study, 3 H-A-804598 was used to determine the ex vivo brain P2X7R occupancy of different P2X7R antagonists, indicating that this class of molecules crosses the blood-brain barrier and supporting the feasibility of in vivo visualization of P2X7R with PET in the brain (13)(14)(15). An additional hurdle, however, is the P2X7R interspecies difference reported for several molecules, giving rise to different binding affinities for mouse, rat, and human P2X7R (hP2X7R) (16)(17)(18).…”