Pharmacological characterization of a novel, orally available GluN2B antagonist JNJ‐63612445

Abstract

IntroductionBlockade of GluN2B (NR2B)‐containing NMDA receptors has been proposed as a therapy for a number of neurological and psychiatric diseases including mood disorders. A number of GluN2B antagonists have been identified and developed over the last three decades. These compounds, however, have significant limitations in regard to their selectivity or drug‐like properties (e.g. oral bioavailability).MethodsThe pharmacology of JNJ‐63612445 was explored using in‐vitro assays (calcium mobilization, competitive radioligand binding, electrophysiology), ex‐vivo slice autoradiography and in‐vivo electrophysiology (synaptic transmission and plasticity) and behavior.ResultsJNJ‐63612445 is a high affinity (pKi=8.0), potent (pIC50=7.8) and selective negative allosteric modulator of GluN2B receptors. Upon oral dosing, the compound occupied GluN2B receptors in rat hippocampus in time‐ and concentration‐dependent manner, reaching 50% occupancy at the plasma concentration of 443 ng/ml. JNJ‐63612445 at 1 μM blocked 54% of NMDA receptor‐mediated EPSC in rat neonatal slices similar to other GluN2B antagonists. The compounds at the dose 10 mg/kg s.c. inhibited in vivo long‐term depression measured in the CA1 of anesthetized rats without effects on the basal synaptic transmission. Given orally at the dose 30 mg/kg in mice, the compound significantly reduces immobility time in a tail‐suspension test, while occupying approximately 89% of the GluN2B receptors in the hippocampus.ConclusionsJNJ‐63612445 represents an example of new generation of potent, selective, and orally available GluN2B antagonists.Support or Funding InformationFunding informationAuthors are full time employees of Janssen Research & Development, LLC. The research was funded by the company.