Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
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DOI：
10.1124/jpet.111.189068
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Stensbol, T. Bryan
中科院分区：
文献类型：
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作者：
Mork, A.;Pehrson, A.;Stensbol, T. Bryan
1-[2-（2,4-二甲基苯基-磺胺基）-苯基]-哌嗪（Lu AA21004）是一种人(h) 5-羟色胺（5-HT）（3A）受体拮抗剂（K-i = 3.7 nM）、h5-HT7受体拮抗剂（K-i = 19 nM）、h5-HT1B受体部分激动剂（K-i = 33 nM）、h5-HT1A受体激动剂（K-i = 15 nM）和人5-HT转运体（SERT）抑制剂（K-i = 1.6 nM） （J Med Chem 54:3206-3221, 2011）。在这里，我们使用基于全细胞camp的实验证实Lu AA21004是部分h5-HT1B受体激动剂[EC50 = 460 nM，内在活性= 22%]，并证明Lu AA21004是大鼠(r) 5-HT7受体拮抗剂（K-i = 200 nM, IC50 = 2080 nM）。在体内，Lu AA21004在皮下给药后占据r5-HT1B受体和rSERT (ED50分别为3.2和0.4 mg/kg)，并且在bezald - jarisch反射试验中是5-HT3受体拮抗剂（ED50 = 0.11 mg/kg s.c）。在大鼠微透析实验中，Lu AA21004 （2.5-10.0 mg/kg s.c）增加了内侧前额叶皮层和海马腹侧的细胞外5-HT、多巴胺和去甲肾上腺素。Lu AA21004 （5mg /kg /天，连续3天；皮下微泵），相当于41%的rSERT占用，显著增加了腹侧海马的细胞外5- ht。此外，5-HT3受体拮抗剂昂丹司琼增强了西酞普兰诱导的细胞外5-HT水平的升高。Lu AA21004在大鼠强迫游泳（弗林德斯敏感线）和社会互动和条件恐惧试验中具有抗抑郁和抗焦虑样作用（最小有效剂量：7.8、2.0和3.9 mg/kg）。综上所述，Lu AA21004通过SERT抑制和5-HT受体调节两种药理方式介导其药理作用。在体内，这导致几种神经递质和抗抑郁药和抗焦虑药样物质的释放增加，其剂量除了SERT外还占据靶点。Lu AA21004的多模态活性谱不同于目前的抗抑郁药。
1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K-i = 3.7 nM), h5-HT7 receptor antagonist (K-i = 19 nM), h5-HT1B receptor partial agonist (K-i = 33 nM), h5-HT1A receptor agonist (K-i = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K-i = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT1B receptor agonist [EC50 = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT7 receptor antagonist (K-i = 200 nM and IC50 = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT1B receptor and rSERT (ED50 = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT3 receptor antagonist in the Bezold-Jarisch reflex assay (ED50 = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT3 receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant-and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant-and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.