LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor
LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor
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DOI：
10.1016/j.neulet.2010.06.036
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发表时间：
2010-08-30
影响因子：
2.5
通讯作者：
Perrone, Roberto
中科院分区：
文献类型：
--
作者：
Hedlund, Peter B.;Leopoldo, Marcello;Perrone, Roberto
我们已经确定了新的5-羟色胺5-HT 7受体激动剂N-（4-氰基苯甲基）-4-（2-二苯基）-1-哌嗪己酰胺（LP-211）对一组5-HT受体亚型进行放射性配体结合试验。还通过检查其对缺乏5-HT 7受体的小鼠的体温调节的作用在体内评价化合物。（5-HT 7-/-）及其5-HT 7 +/+同胞对照。在两种基因型的小鼠中进行处置研究。结果表明，LP-211具有脑渗透性，经代谢降解为1-（2-二苯基）哌嗪（RA-7）。体外结合试验表明，RA-7具有更高的5-HT 7受体亲和力比LP-211和一个更好的选择性的5-HT受体亚型的面板。在体内，证明LP-211和较低程度的RA-7在5-HT 7 +/+小鼠中诱导体温降低，但在5-HT 7-/-小鼠中不诱导体温降低。我们的研究结果表明，LP-211可用作体内5-HT 7受体激动剂。(C)2010爱思唯尔爱尔兰有限公司版权所有。
We have determined the pharmacological profile of the new serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211) Radioligand binding assays were performed on a panel of 5-HT receptor subtypes The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 receptor (5-HT7-/-) and their 5-HT7+/+ sibling controls Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7+/+ but not in 5-HT7-/- mice. Our results suggest that LP-211 can be used as a 5-HT7 receptor agonist in vivo. (C) 2010 Elsevier Ireland Ltd. All rights reserved.