LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor

被引：74
作者：
Hedlund, Peter B. [1 ]
Leopoldo, Marcello [2 ]
Caccia, Silvio [3 ]
Sarkisyan, Gor [1 ]
Fracasso, Claudia [3 ]
Martelli, Giuliana [3 ]
Lacivita, Enza [2 ]
Berardi, Francesco [2 ]
Perrone, Roberto [2 ]
机构：
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] Univ Bari, Dipartimento Farmacochim, I-70125 Bari, Italy
[3] Ist Ric Farmacol Mario Negri, I-20156 Milan, Italy
来源：
NEUROSCIENCE LETTERS | 2010年 / 481卷 / 01期
关键词：
Serotonin; 5-HT7; receptor; Agonist; LP-211; RA-7; Brain distribution; Body temperature; KNOCKOUT MICE; ANTAGONIST; CYCLASE; BINDING;
D O I：
10.1016/j.neulet.2010.06.036
中图分类号：
Q189 [神经科学];
学科分类号：
071006 ;
摘要：
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.
引用
收藏
页码：12 / 16
页数：5
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