XAP044 is an antagonist of the metabotropic glutamate (mGlu) receptor 7 (mGluR7), inhibiting lateral amygdala long term potentiation in brain slices from wild-type mice with an IC50 value of 88 nM. This effect is absent in mGluR7-deficient mice. XAP044 demonstrates good brain penetrance, producing wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy in rodent behavioral tests.
XAP 044 is a potent mGlu7 antagonist used in the treatment of anxiety and depression in mice (1,2). Applications towards stress, autism and drug abuse are also potential uses.
previous study showed that in contrast to all previous mglu7-selective drugs, xap044 did not act through the seven-transmembrane region but rather via a binding pocket localized in mglu7's extracellular venus flytrap domain, a region identified for orthosteric agonist binding, which was suggested by the chimeric receptor studies in recombinant cell line assays [1].
in rodent behavioral paradigms, xap044 demonstrated good brain exposure and wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy. in addition, xap044 could reduce freezing during acquisition of pavlovian fear and innate anxiety, which was consistent with the phenotypes of mglu7-deficient mice. moreover, xap044 was able to inhibit lateral amygdala long term potentiation (ltp) in brain slices from wild type mice with a half-maximal blockade at 88 nm. it was alos found that there was no effect of xap044 on ltp of mglu7-deficient mice, suggesting that such pharmacological effect was mglu7-dependent [1].
[1] c. e. gee, d. peterlik, c. neuh user, et al. blocking metabotropic glutamate receptor subtype 7 (mglu7) via the venus flytrap domain (vftd) inhibits amygdala plasticity, stress, and anxiety-related behavior. the journal of biological chemisty 289(16), 10975-10987 (2014).
