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.
XAP044是一种mGlu7选择性拮抗剂，IC50值为5.5μM[1]。XAP044通过结合于mGlu7受体的细胞外 Venus Flytrap 结构域（通常为正构激动剂结合区域）来阻断mGlu7信号传导[2]。XAP044目前已作为模型化合物广泛应用于开发抑制mGlu7活性的系列衍生物[3]。
在体内，单次皮下注射30 mg/kg剂量的XAP044可在2小时内逆转神经病理性疼痛小鼠模型的机械性痛觉过敏，并改善焦虑和抑郁样行为[4]。单次腹腔注射60mg/kg剂量的XAP044 30分钟，可缓解小鼠的生理性和先天性焦虑抑郁样行为，并减少恐惧条件反射习得阶段的僵直行为[5]。通过微型渗透泵以0.11μl/h的速率脑室输注100μM的XAP044连续20天，能改善慢性从属群体饲养（CSC）诱导的雄性C57BL/6小鼠下丘脑-垂体-肾上腺轴功能障碍、胸腺萎缩及先天性焦虑增强[6]。