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首页> 美国卫生研究院文献>Pharmacology Research Perspectives >The arylpiperazine derivatives N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide and N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide exert a long-lasting inhibition of human serotonin 5-HT7 receptor binding and cAMP signaling
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The arylpiperazine derivatives N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide and N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide exert a long-lasting inhibition of human serotonin 5-HT7 receptor binding and cAMP signaling

机译：芳基哌嗪衍生物N-（4-氰基苯基甲基）-4-（2-二苯基）-1-哌嗪己酰胺和N-苄基-4-（2-二苯基）-1-哌嗪己酰胺对人5-羟色胺5-HT7具有持久的抑制作用受体结合和cAMP信号转导

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We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211) previously identified as a high-affinity brain penetrant ligand for 5-hydroxytryptamine (serotonin) type 7 (5-HT7) receptors, and its analog N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide (MEL-9). Both ligands exhibited competitive displacement of [3H]-(2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine ([3H]-SB-269970) radioligand binding and insurmountable antagonism of 5-carboxamidotryptamine (5-CT)-stimulated cyclic adenosine monophosphate (cAMP) signaling in human embryonic kidney (HEK293) cells stably expressing human 5-HT7 receptors. They also inhibited forskolin-stimulated adenylate cyclase activity in 5-HT7-expressing HEK293 cells but not in the parental cell line. The compounds elicited long-lasting (at least 24 h) concentration-dependent inhibition of radioligand binding at 5-HT7-binding sites in whole-cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent compound removal. In cAMP assays, pretreatment of cells with the compounds rendered 5-HT7 receptors unresponsive to 5-CT and also rendered 5-HT7-expressing HEK293 cells unresponsive to forskolin. Compound 1-(2-biphenyl)piperazine (RA-7), a known active metabolite of LP-211 present in vivo, was able to partially inhibit 5-HT7 radioligand binding in a long-lasting irreversible manner. Hence, LP-211 and MEL-9 were identified as high-affinity long-acting inhibitors of human 5-HT7 receptor binding and function in cell lines. The detailed in vitro characterization of these two pharmacological tools targeting 5-HT7 receptors may benefit the study of 5-HT7 receptor function and it may lead to the development of novel selective pharmacological tools with defined functional properties at 5-HT7 receptors.
机译：我们对两种芳基哌嗪衍生物化合物N-（4-氰基苯基甲基）-4-（2-二苯基）-1-哌嗪己酰胺（LP-211）进行了详细的体外药理学表征，先前确定其为5的高亲和性脑渗透配体-羟色胺（5-羟色胺）7型（5-HT7）受体及其类似物N-苄基-4-（2-二苯基）-1-哌嗪己酰胺（MEL-9）。两种配体均显示[ 3 H]-（2R）-1-[（3-羟基苯基）磺酰基] -2- [2-（4-甲基-1-哌啶基）乙基]吡咯烷的竞争性取代（[ 3 H] -SB-269970）稳定表达人类胚胎肾脏（HEK293）细胞中5-羧酰胺基色胺（5-CT）刺激的环磷酸腺苷（cAMP）信号的放射性配体结合和不可克服的拮抗作用人5-HT7受体。它们还在表达5-HT7的HEK293细胞中抑制了毛喉素刺激的腺苷酸环化酶活性，但在亲本细胞系中却没有抑制。在用化合物对细胞进行预处理并随后去除化合物后，在全细胞放射性配体结合测定中，化合物在5-HT7结合位点引起了对放射性配体结合的长期（至少24小时）浓度依赖性抑制。在cAMP分析中，用化合物预处理细胞会使5-HT7受体对5-CT无反应，并且使表达5-HT7的HEK293细胞对毛喉素无反应。化合物1-（2-联苯基）哌嗪（RA-7）是体内存在的LP-211的一种已知活性代谢产物，能够以长期不可逆的方式部分抑制5-HT7放射性配体的结合。因此，LP-211和MEL-9被鉴定为人5-HT7受体结合和在细胞系中起作用的高亲和力长效抑制剂。这两种针对5-HT7受体的药理学工具的详细体外表征可能有益于5-HT7受体功能的研究，并且可能导致开发出具有针对5-HT7受体定义的功能特性的新型选择性药理学工具。

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