XAP044

XAP044 is a mGluR7 antagonist.

The function of metabotropic glutamate receptor subtype 7 (mGlu7), an critical presynaptic regulator of neurotransmission in the mammalian CNS, has been linked to drug abuse, anxiety, autism, as well as depression. However, it is difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as limbic cortex and amygdala.

In vitro: 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 vivo: 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].

Clinical trial: Up to now, XAP044 is still in the preclinical development stage.

Reference:
[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).