Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice

Abstract

Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu7 subtype. Here, genetic mGlu7 ablation, short-term pharmacological mGlu7 blockade, as well as siRNA-mediated knockdown of mGlu7 were shown to result in an acute anti-stress, antidepressant- and anxiolytic-like phenotype in mice. Moreover, we recently revealed a prominent stress-protective effect of genetic mGlu7 ablation also with respect to chronic psychosocial stress. In addition, we are able to demonstrate in the present study that the chronic pharmacological blockade of mGlu7 interferes with various chronic stress-induced alterations. For this, we used the chronic subordinate colony housing (CSC), a mouse model of chronic male subordination, in combination with chronic treatment with the mGlu7-selective orthosteric-like antagonist XAP044 (7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one). Interestingly, XAP044 dose-dependently ameliorates hypothalamic–pituitary–adrenal axis dysfunctions, thymus atrophy, as well as the CSC-induced increase in innate anxiety. Taken together, our findings provide further evidence for the role of mGlu7 in chronic psychosocial stress-induced alterations and suggests the pharmacological blockade of mGlu7 as a promising therapeutic approach for the treatment of chronic stress-related pathologies in men.

Novel Inhibitory Site Revealed by XAP044 Mode of Action on the Metabotropic Glutamate 7 Receptor Venus Flytrap Domain

“…Docking in the third orientation along the α6 helix looked promising (Figure 14). As for option 2, molecular characteristics of this docking are in agreement with the SAR data: (1) H-bonds with S160 and S229, (2) hydrophobic contacts with A183, P184, K233 in an out-of-plane conformation, (3) halogen bonds 35 with S237, Q240, (4) a restricted environment around the iodophenyl, (5) mGlu7 selectivity because of K233 and S237 interactions. The complex remained stable in a 5 ns molecular dynamics simulation.…”

“…The discovery of mGlu7 homodimer ligands has been hampered by its difficult activation, despite its value as a therapeutic target in several CNS diseases. , Yet, screening campaigns have yielded some allosteric modulators, including XAP044 discovered by scientists at Novartis . They showed that XAP044 is an mGlu7 receptor antagonist with the particularity that it does not bind to the receptor transmembrane domain as most other mGluR modulators but to the extracellular domain.…”