XAP044 is a potent mGlu7 selective antagonist, with an IC50 value of 5.5μM[1]. XAP044 blocks mGlu7 signaling via a binding pocket localized in mGlu7's extracellular Venus flytrap domain, a region generally known for orthosteric agonist binding[2]. XAP044 has been widely used as a model compound for the development of a series of related derivatives to inhibit mGlu7 activity[3].
In vivo, a single subcutaneous injection of XAP044(30mg/kg) within 2 hours reversed mechanical hyperalgesia and ameliorated anxieties and depression-like behaviors in a mouse model of neuropathic pain[4]. A single intraperitoneal injection of XAP044 at a dose of 60mg/kg for 30 minutes alleviated physiological and congenital anxist-and depression-like behaviors in mice, and reduced freezing behavior during the acquisition phase of fear conditioning[5]. Intracerebroventricular infusion of 100µM XAP044 at a rate of 0.11µl/h via a micro-osmotic pump for 20 days improved hypothalamic-pituitary-adrenal axis dysfunction, thymic atrophy, and chronic subordinate colony housing (CSC)-induced increases in congenital anxiety in male C57BL/6 mice[6].
References:
[1] Fisher N M, Seto M, Lindsley C W, et al. Metabotropic glutamate receptor 7: a new therapeutic target in neurodevelopmental disorders[J]. Frontiers in molecular neuroscience, 2018, 11: 387.
[2] Palazzo E, Marabese I, Luongo L, et al. Nociception modulation by supraspinal group III metabotropic glutamate receptors[J]. Journal of Neurochemistry, 2017, 141(4): 507-519.
[3] Cristiano N, Cabayé A, Brabet I, et al. Novel inhibitory site revealed by XAP044 Mode of Action on the metabotropic glutamate 7 receptor Venus Flytrap Domain[J]. Journal of medicinal chemistry, 2024, 67(14): 11662-11687.
[4] Palazzo E, Romano R, Luongo L, et al. MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice[J]. Pain, 2015, 156(6): 1060-1073.
[5] Gee C E, Peterlik D, Neuhäuser C, et al. Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior[J]. Journal of Biological Chemistry, 2014, 289(16): 10975-10987.
[6] Estrela K A R, Senninger L, Arndt J, et al. Blocking metabotropic glutamate receptor subtype 7 via the Venus Flytrap Domain promotes a chronic stress-resilient phenotype in mice[J]. Cells, 2022, 11(11): 1817.