Localisation of melanin-concentrating hormone receptor 1 in rat brain and evidence that sleep parameters are not altered despite high central receptor occupancy
Localisation of melanin-concentrating hormone receptor 1 in rat brain and evidence that sleep parameters are not altered despite high central receptor occupancy
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DOI：
10.1016/j.ejphar.2009.06.009
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发表时间：
2009-08-15
影响因子：
5
通讯作者：
Katugampola, Sidath D.
中科院分区：
文献类型：
--
作者：
Able, Sarah L.;Ivarsson, Magnus;Katugampola, Sidath D.
本研究描述了一种优化的放射自显影分析，它提供了一种测量天然组织中黑色素浓缩激素受体1(MCH(1))拮抗剂的体外效力及其体外受体占有率的方法。初步定位研究表明，MCH(1)受体放射性配基[(125)1]-S36057与大鼠尾壳核结合，特异性结合率为60%。在体外，Mch(1)受体拮抗剂GW3430、SNAP-94847和4‘-{[1-(cyclopropylmethyl)piperidin-4-ylidene][5-fluoro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}biphenyl-3-carbonitrile(简称化合物A)对[(125)I]-S36057的结合具有浓度依赖性抑制作用，其亲和力顺序为化合物A&gT；GW3430。在体外占位实验中，化合物A灌胃给大鼠可浓度依赖性地抑制[(125)I]-S36057与大鼠尾壳核的特异性结合。30 mg/kg时占有率达87+/-11%，估算ED(50)为9.3 mg/kg，相当于40 NM的游离血药浓度。由于MCH已被报道在睡眠周期的调节中发挥作用，因此研究了化合物A对睡眠参数的影响。然而，化合物A在接近最大受体占有率的暴露下，未能证明对遥测大鼠的睡眠/觉醒模式有任何影响。我们的结论是，我们的体外受体占有率试验适合于选择中央穿透性的MCH(1)受体拮抗剂，尽管有很高的受体占有率，但选择性的MCH(1)受体拮抗剂化合物A未能引起睡眠脑电(EEG)参数的任何变化。(C)2009爱思唯尔B.V.保留所有权利。
The present study describes the optimisation of an autoradiography assay that provides a means to measure the in vitro potency of melanin-concentrating hormone receptor 1 (MCH(1)) antagonists in native tissues and their ex vivo receptor occupancy. Initial localisation studies demonstrated that the MCH(1) receptor radioligand [(125)1]-S36057 bound to rat caudate putamen with specific binding of consistently >60%. In vitro, the MCH(1) receptor antagonists GW3430, SNAP-94847 and 4'-{[1-(cyclopropylmethyl)piperidin-4-ylidene] [5-fluoro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}biphenyl-3-carbonitrile (referred to as Compound A) exhibited concentration dependent inhibition of the specific binding of [(125)I]-S36057, with a rank order of affinity of SNAP-94847 > Compound A>GW3430. In an ex vivo occupancy assay, Compound A dosed orally to rats caused a concentration dependent inhibition of the specific binding of [(125)I]-S36057 to rat caudate putamen. The occupancy reached 87 +/- 11% at 30 mg/kg and the estimated ED(50) was 9.3 mg/kg, which was equivalent to a free plasma concentration of 40 nM. As MCH has been reported to play a role in the regulation of the sleep cycle, the effect of Compound A on sleep parameters was investigated. However Compound A, at exposures that achieved near maximal receptor occupancy, failed to demonstrate any effects on the sleep/wake pattern in telemetered rats. We conclude that our ex vivo receptor occupancy assay is suitable for selecting centrally penetrant MCH(1) receptor antagonists and that, despite high levels of receptor occupancy, the selective MCH(1) receptor antagonist Compound A failed to elicit any changes in sleep electroencephalogram (EEG) parameters. (C) 2009 Elsevier B.V. All rights reserved.