Deciphering the Role of JNJ-47965567: A Centrally Acting P2X7 Receptor Antagonist in CNS Pathophysiology

The P2X7 receptor, a ligand-gated ion channel in the CNS, has been implicated in various neurological conditions, including neuropsychiatric disorders, neurodegeneration, and chronic pain. This study focused on JNJ-47965567, a novel and selective P2X7 antagonist with the ability to cross the blood-brain barrier.

A range of in vitro assays were conducted to evaluate the potency and selectivity of JNJ-47965567, including calcium flux, radioligand binding, electrophysiology, and IL-1β release tests in both recombinant and native systems. The compound demonstrated high affinity for the human P2X7 receptor with a pKi of 7.9 ± 0.07 and selectivity over other species. It effectively reduced IL-1β release in human blood, monocytes, and rat microglia, indicating its potency in native systems.

Ex vivo receptor binding autoradiography and in vivo blockade of Bz-ATP induced IL-1β release in the rat brain confirmed the target engagement of JNJ-47965567. Furthermore, the compound showed efficacy in preclinical models, attenuating amphetamine-induced hyperactivity and exhibiting significant effects in a rat model of neuropathic pain. However, it did not demonstrate efficacy in the forced swim test, a standard model for depression.

In conclusion, JNJ-47965567 is a centrally active, high-affinity P2X7 antagonist that can be utilized to investigate the role of central P2X7 in CNS pathophysiology in rodent models.