Abstract

Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in schizophrenia patients. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu₅) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu₅ positive allosteric modulators (PAMs), VU0364289, and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca²⁺ mobilization and ERK1/2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu₅ allosteric binding site and high selectivity for mGlu₅. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu₅ PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal mediated memory task, and elicited changes in EEG dynamics commensurate with pro-cognitive effects. Collectively, these data support and extend the role for the development of novel mGlu₅ PAMs for the treatment