Biased mGlu 5 -Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu 5 Modulation of NMDAR Currents

Abstract

Summary Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq–mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy.

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

“…22 Consistent with current antipsychotics, 17a increased prefrontal dopamine levels (MED 10 mg/kg po) and absolutely no effect on prolactin levels in rats or catelpsy. 21 In addition, 17a also induced septal cFos mRNA 153% (40 mg/kg po).…”

“…administration as well as seizure activity. 22 In sharp contrast, we recently reported that 17a, a pure mGlu 5 PAM with high efficacy and large fold-shift, at a high dose of 120 mg/kg po for four consecutive days, did not induce FJC staining nor did it induce seizures in mice at doses >100-fold over the MED in AHL (CNS NOAEL of 108−147 μM·h).…”

“…From this effort, 17a emerged as an mGlu 5 PAM with the most balanced profile (vide inf ra) and worthy of further development, with no species differences (activity at rat mGlu 5 was comparable to human (rat EC 50 = 235 nM, pEC 50 = 6.63 ± 0.08, 74 ± 2% Glu Max). 22 The molecular pharmacology profile of 17a is highlighted in Figure 3. In the presence of an EC 20 concentration of glutamate, 17a potentiates the human mGlu 5 response in a concentration-dependent manner resulting in an EC 50 of 260 nM, with 84% Glu Max ( Figure 3A).…”

“…As expected, 17a potentiates DHPG-induced long-term depression (LTD) and induces calcium mobilization and ERK phosphorylation; however, 17a does not potentiate mGlu 5 modulation of NMDA receptor currents nor NMDA receptor-dependent long-term potentiation (LTP), suggesting a unique signal bias for this mGlu 5 PAM that may contribute to the observed, favorable therapeutic window. 22 From a conceptual point of view, it is intriguing that selective mGlu 5 activation can provide antipsychotic and cognition-enhancing efficacy in the absence of potentiating NMDA receptor function. Based on the favorable and unique profile of 17a, human PK predictions, based on trough plasma levels (400 ng/mL) from rat AHL and interspecies allometric scaling, led to predicted human clearance in the range of 1.5 to 3.6 mL/min/kg and with half-life of 10−24 h. 21 Simulations of steady state dosing for 24 h coverage indicated 250−600 mg qd or 100−400 mg bid in man.…”

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

“…electrophysiological responses 5 signaling responses in cell-based assays, but has no efficacy in modulating hippocampal long-term potentiation or N-methyl-D-aspartate receptor currents (Rook et al, 2015). However, VU0409551 has efficacy in preclinical rodent models of psychosis and cognition (Rook et al, 2015), suggesting that biased allosteric modulators of mGlu 5 can possess preclinical efficacy.…”