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

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
Anindya BhattacharyaMichael A Letavic

Abstract

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 blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β 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-1β 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 ...Continue Reading

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Citations

Sep 4, 2019·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Anindya Bhattacharya, Marc Ceusters
Oct 2, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Brandon G ShokoplesErnesto L Schiffrin
Sep 26, 2020·Frontiers in Immunology·Linglin YangAnwen Shao
Jun 17, 2020·Molecular Imaging·Hamideh Zarrinmayeh, Paul R Territo
Feb 1, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Wen-Jun ZhangHong-Liang Luo
Apr 24, 2021·Frontiers in Cellular Neuroscience·Paul R Territo, Hamideh Zarrinmayeh
Oct 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Hui JingBenjamin F Cravatt

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Methods Mentioned

BETA
ELISA
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Clinical Trials Mentioned

NCT03151486

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β Imager
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