Pascal Bonaventure

Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567

An increasing body of evidence suggests that the purinergic receptor P2X, ligand‐gated ion channel, 7 (P2X7) in the CNS may play a key role in neuropsychiatry, neurodegeneration and chronic pain. In this study, we characterized JNJ‐47965567, a centrally permeable, high‐affinity, selective P2X7 antagonist.

Translational Evaluation of JNJ-18038683, a 5-Hydroxytryptamine Type 7 Receptor Antagonist, on Rapid Eye Movement Sleep and in Major Depressive Disorder

In rodents 5-hydroxytryptamine type 7 (5-HT7) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT7 receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT7 blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) < = 12] and from sites with no placebo response (MADRS > = 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.

G-Protein-Coupled Receptor (GPCR)-142 Does Not Contribute to Relaxin-3 Binding in the Mouse Brain: Further Support that Relaxin-3 Is the Physiological Ligand for GPCR135

Relaxin-3 is a recently discovered member of the insulin/relaxin superfamily that has been shown to be the endogenous ligand for G-protein-coupled receptor (GPCR)135 (SALPR). In addition, relaxin-3 has demonstrated affinity and functional agonism for GPCR142 (GPR100) and LGR7 receptors in vitro. Recent evidence suggests GPCR142 is the insulin-like peptide 5 (INSL5) receptor and LGR7 is the actual relaxin receptor. We have recently described a chimeric R3/I5 peptide that selectively activates GPCR135 and GPCR142, but lacks affinity for LGR7. GPCR142 is a pseudogene in the rat, which allowed the use of [125I]-R3/I5 to show GPCR135-like binding sites in the rat central nervous system by autoradiography. However, mouse GPCR142 is a viable gene. In the present study we explore whether GPCR142 is expressed in the mouse brain and whether it is likely to contribute to or interfere with the pharmacological evaluation of relaxin-3 ligands. Competition binding studies confirmed mINSL5 and [125I]-mINSL5 bind to mGPCR142 with high affinity. However, no detectable specific [125I]-mINSL5 binding sites were detected throughout the mouse brain and unlabelled INSL5 did not displace [125I]-R3/I5 binding sites, indicating an absence of detectable GPCR142 binding sites. Consistent with these findings, neither GPCR142 nor INSL5 mRNA were detectable in mouse brain by in situ hybridization. Overall, the distribution of GPCR135 mRNA overlapped with the distribution of GPCR135 binding sites shown by autoradiography using [125I]-R3/I5. GPCR135 mRNA and GPCR135 receptor binding sites are most prominent in the mouse amygdala and hypothalamus. These data suggest that relaxin-3/GPCR135 is the receptor ligand pair with physiological relevance in mouse brain.