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Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

ABSTRACT: Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1? release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1? release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED50 of 0.07?mg/kg. The P2X7 antagonist (3?mg/kg, oral) blocked Bz-ATP-induced brain IL-1? release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30?mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8?mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30?mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1? release and microglial activation leading to efficacy in two models of anhedonia in rodents.

SUBMITTER: Bhattacharya A

PROVIDER: S-EPMC6224414 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

Bhattacharya Anindya A Lord Brian B Grigoleit Jan-Sebastian JS He Yingbo Y Fraser Ian I Campbell Shannon N SN Taylor Natalie N Aluisio Leah L O'Connor Jason C JC Papp Mariusz M Chrovian Christa C Carruthers Nicholas N Lovenberg Timothy W TW Letavic Michael A MA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180709 13

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blo ...[more]

PMID: 30026598

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Project description:BACKGROUND: Acetylcholine receptor type ligand-gated ion channels (ART-LGIC; also known as Cys-loop receptors) are a superfamily of proteins that include the receptors for major neurotransmitters such as acetylcholine, serotonin, glycine, GABA, glutamate and histamine, and for Zn2+ ions. They play a central role in fast synaptic signaling in animal nervous systems and so far have not been found outside of the Metazoa. RESULTS: Using sensitive sequence-profile searches we have identified homologs of ART-LGICs in several bacteria and a single archaeal genus, Methanosarcina. The homology between the animal receptors and the prokaryotic homologs spans the entire length of the former, including both the ligand-binding and channel-forming transmembrane domains. A sequence-structure analysis using the structure of Lymnaea stagnalis acetylcholine-binding protein and the newly detected prokaryotic versions indicates the presence of at least one aromatic residue in the ligand-binding boxes of almost all representatives of the superfamily. Investigation of the domain architectures of the bacterial forms shows that they may often show fusions with other small-molecule-binding domains, such as the periplasmic binding protein superfamily I (PBP-I), Cache and MCP-N domains. Some of the bacterial forms also occur in predicted operons with the genes of the PBP-II superfamily and the Cache domains. Analysis of phyletic patterns suggests that the ART-LGICs are currently absent in all other eukaryotic lineages except animals. Moreover, phylogenetic analysis and conserved sequence motifs also suggest that a subset of the bacterial forms is closer to the metazoan forms. CONCLUSIONS: From the information from the bacterial forms we infer that cation-pi or hydrophobic interactions with the ligand are likely to be a pervasive feature of the entire superfamily, even though the individual residues involved in the process may vary. The conservation pattern in the channel-forming transmembrane domains also suggests similar channel-gating mechanisms in the prokaryotic versions. From the distribution of charged residues in the prokaryotic M2 transmembrane segments, we expect that there will be examples of both cation and anion selectivity within the prokaryotic members. Contextual connections suggest that the prokaryotic forms may function as chemotactic receptors for low molecular weight solutes. The phyletic patterns and phylogenetic relationships suggest the possibility that the metazoan receptors emerged through an early lateral transfer from a prokaryotic source, before the divergence of extant metazoan lineages.

Dataset Information

Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

Publications

Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

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