Synthesis and Pharmacological Characterization of Two Novel, Brain Penetrating P2X₇ Antagonists

Abstract

The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

“…Kim et al (2013) have shown, however, that αS oligomers spontaneously secreted by a neuroblastoma cell line had the potential to activate TLR-2 in microglial cells whereas fibrils produced from recombinant αS were unable to do so. Glutamate release induced by αSa was also significantly curtailed by JNJ, a synthetic antagonist for purinergic P2X7 receptors (Letavic et al, 2013), which is reminiscent to previous studies showing that oligomeric forms of αS bind directly to this receptor subtype . Glutamate release induced by αSa was also significantly curtailed by JNJ, a synthetic antagonist for purinergic P2X7 receptors (Letavic et al, 2013), which is reminiscent to previous studies showing that oligomeric forms of αS bind directly to this receptor subtype .…”

“…In the same setting, we also tested the impact of JNJ (20 μM), a synthetic antagonist for purinergic P2X7 receptors (Letavic et al, 2013). To address this point, microglial cells were exposed to αSa (70 μg/ml) in the presence or not of MAb mTLR2 (2.5 μg/ml), an antagonistic antibody for TLR2 receptors (Chen, Xie, Turkson, & Zhuang, 2015).…”

“…To address this point, microglial cells were exposed to αSa (70 μg/ml) in the presence or not of MAb mTLR2 (2.5 μg/ml), an antagonistic antibody for TLR2 receptors (Chen, Xie, Turkson, & Zhuang, 2015). In the same setting, we also tested the impact of JNJ (20 μM), a synthetic antagonist for purinergic P2X7 receptors (Letavic et al, 2013). Figure 2b shows that glutamate release induced by αSa was markedly 3.3 | Glutamate release induced by αSa in microglial cells occurs through activation of the X − c antiporter system Next, we tested the possibility that αSa could stimulate glutamate release by activating the antiporter system Xc − , a membrane protein that imports into the cells the amino acid L-cystine, the oxidized form of cysteine, and exports L-glutamate in a 1:1 ratio (Lewerenz et al, 2013;Soria et al, 2016).…”

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

“…These newer druglike antagonists are particularly important for the purinergic field, because the first generation of antagonists was generally designed for in vitro, rather than therapeutic, use. Furthermore, many of the original antagonists are subject to degradation when used in vivo or are predicted to have poor pharmacokinetics (Friedle et al, 2010;Jiang, 2012) , and N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide (AACBA; also known as GSK314181) (Broom et al, 2008), the cyanoguanidine derivative (Honore et al, 2006), the cyclic imide 3- [1-[[(39-nitro[1,19-biphenyl]-4-yl)oxy]methyl]-3-(4-pyridinyl) propyl]-2,4-thiazolidinedione (AZ11645373) (Stokes et al, 2006), and the nicotinamide derivative N-([4-(4-phenyl-piperazin-1-yl]tetrahydro-2H-pyran-4-yl)-methyl)-2-(phenyl-thio) nicotinamide (JNJ-47965567) (Letavic et al, 2013). The concentration responses of some of these specific antagonists (including A438079 and AZ11645373) have been determined at native murine P2X7 receptors Pupovac et al, 2013b), which is useful for their in vivo application.…”

Medicinal chemistry of adenosine, P2Y and P2X receptors

“…These structures indicate that the P2X7 receptor tolerates very bulky residues, like cycloheptyl, adamantyl and related ring systems. Several other P2X7 antagonists that penetrate well into the brain have recently been described, including GSK1482160 ( 146 ), which has been prepared in 11 C-labeled form to provide a ligand for positron emission tomography (PET) studies (Gao et al, 2015), JNJ-47865567 ( 147 ) (Letavic et al, 2013; Bhattacharya et al, 2013), JNJ-42253432 ( 148 ) (Lord et al, 2014) and the triazolopyrazinylmethanone 149 (Rudolph et al, 2015). A novel, useful 3H-labeled antagonist radioligand, [ 3 H]JNJ-54232334 ( 150 ) has been reported (Lord et al, 2015).…”