Development of novel, cns penetrant mglu3 selective negative allosteric modulator probes derived from a closely related mglu5 positive allosteric modulator

Abstract

Metabotropic glutamate (mGlu) receptors are examples of family C G-protein-coupled receptors that possess vast roles in the pathophysiology of central nervous system (CNS) disorders. In order to fully understand the mGlu receptors’ roles in disease, it is necessary to develop potent and highly selective probes to individually target the mGlu receptor subtypes. At the outset of this project, there existed no suitable probes to selectively target metabotropic glutamate receptor 3 (mGlu3). Herein we report the discovery and SAR of a novel mGlu3 negative allosteric modulator (NAM) probe (VU0463597) with modest selectivity (~5- to 15-fold) versus fellow group II mGlu receptor, mGlu2. The mGlu3 NAM was discovered via a ‘molecular switch’ from a closely related, potent mGlu5 positive allosteric modulator (PAM), VU0092273. This mGlu3 NAM (VU0463597) displays an IC50 value of 649 nM and is inactive on mGlu5.