Preclinical Evaluation of Melanin-Concentrating Hormone Receptor 1 Antagonism for the Treatment of Obesity and Depression
Preclinical Evaluation of Melanin-Concentrating Hormone Receptor 1 Antagonism for the Treatment of Obesity and Depression
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DOI：
10.1124/jpet.108.143362
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发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Witkin, Jeffrey M.
中科院分区：
文献类型：
--
作者：
Gehlert, Donald R.;Rasmussen, Kurt;Witkin, Jeffrey M.
哺乳动物神经肽，黑色素浓集激素，与两个G蛋白偶联受体，黑色素浓集激素受体（MCHR）1和MCHR 2相互作用;然而，只有MCHR 1在大鼠和小鼠中表达。在本研究中，我们在临床前模型中评估了MCHR 1拮抗作用，认为其可预测抗肥胖和抗抑郁活性。选择性MCHR 1拮抗剂GW 803430 [6-（4-氯-苯基）-3-[3-甲氧基-4-（2-吡咯烷-1-基-乙氧基）-苯基]-3H-噻吩并[3，2-d]嘧啶-4-酮]的中枢活性使用离体结合与放射自显影进行评价。GW 803430的有效剂量（1和3 mg/kg p.o.）在饮食诱导的肥胖大鼠的14天研究中，随后在小鼠和大鼠中评价GW 803430的抗抑郁样作用。在小鼠强迫游泳试验中，急性和亚慢性给药减少了3（急性）和3和10（慢性）mg/kg p.o.剂量下的不动时间，这种效应在MCHR 1（-/-）小鼠中不存在。联合亚有效剂量的GW 803430（0.3和1 mg/kg p.o.）丙咪嗪（5 mg/kg）产生了强有力的抗抑郁样反应。该化合物在10 mg/kg p.o.的剂量下在悬尾试验中也具有活性。GW803430（30 mg/kg p.o.）在第2周和第3周显著减少顺从行为，这是一种可以预测抗抑郁药起效的顺从行为模型。GW 803430在3、10和30 mg/kg p.o.剂量下减少小鼠的大理石掩埋，一种检测抗焦虑作用的检测方法。因此，GW 803430在大鼠和小鼠体内以竞争中心MCHR 1的剂量产生稳健的抗肥胖和抗抑郁样作用。因此，MCHR 1应该被认为是未来药物发现工作的一个有前途的目标。
The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d] pyrimidin-4-one], was evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 14-day study of diet-induced obese rats. GW803430 was evaluated subsequently for antidepressant-like effects in mice and rats. Acute and subchronic administration reduced immobility time in the mouse forced-swim test at doses of 3 (acute) and 3 and 10 (chronic) mg/kg p.o., an effect that was absent in MCHR1(-/-) mice. Combined subeffective doses of GW803430 (0.3 and 1 mg/kg p.o.) and imipramine (5 mg/kg) produced a robust antidepressant-like response. The compound was also active in the tail suspension test at a dose of 10 mg/kg p.o. GW803430 (30 mg/kg p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of submissive behavior that may predict antidepressant onset. GW803430 decreased marble burying in mice at doses of 3, 10, and 30 mg/kg p.o., an assay that detects anxiolytic-like effects. Thus, GW803430 produces robust antiobesity and antidepressant-like effects in rats and mice at doses that compete for central MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for future drug discovery efforts.