Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D3 receptor Ligands
Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D3 receptor Ligands
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DOI：
10.1021/jm020952a
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发表时间：
2002-12-19
影响因子：
7.3
通讯作者：
Tortorella, V
中科院分区：
文献类型：
--
作者：
Leopoldo, M;Berardi, F;Tortorella, V
苯甲酰胺PB12（N - [2 - [4 - (4 - 氯苯基)哌嗪 - 1 - 基]乙基] - 3 - 甲氧基苯甲酰胺）(1)，已被报道为一种强效且选择性的多巴胺D - 4受体配体，为寻找可能产生D - 3受体亲和力的结构特征而进行了修饰。与N - 1哌嗪环相连的芳环的改变导致了2 - 甲氧基苯基和2,3 - 二氯苯基衍生物（化合物6和13）的发现，它们显示出中等的D3亲和力（Ki分别为145和31 nM）。化合物1、6和13中中间烷基链的延长提高了对D3受体的结合亲和力并降低了对D4的亲和力（化合物18 - 26）。在这些后面的化合物中，N - [4 - [4 - (2,3 - 二氯苯基)哌嗪 - 1 - 基]丁基] - 3 - 甲氧基苯甲酰胺(19)通过替换2,3 - 二氯苯基部分（化合物27 - 30）或3 - 甲氧基苯基环（化合物31 - 41）进一步被修饰。通过这种方式，我们鉴定出了几种高亲和力的D - 3配体（0.13 nM < Ki值 < 4.97 nM），它们对D - 2、D - 4、5 - HT1A和α(1)受体具有高选择性。此外，N - [4 - [4 - (2,3 - 二甲基苯基)哌嗪 - 1 - 基]丁基] - 3 - 甲氧基苯甲酰胺(27)和N - [4 - [4 - (2,3 - 二氯苯基)哌嗪 - 1 - 基]丁基] - 7 - 甲氧基 - 2 - 苯并呋喃甲酰胺(41)由于其亲和力值、亲脂性特性以及在O - 甲基位置进行C - 11标记的可能性，似乎是正电子发射断层扫描（PET）的有价值的候选物。
The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl] ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D-4 receptor ligand, has been modified searching for structural features that could lead to D-3 receptor affinity. Changes in the aromatic ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D3 affinity (K-i = 145 and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13 improved binding affinity for the D3 receptor and decreased the D4 affinity (compounds 18-26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way, we identified several high-affinity D-3 ligands (0.13 nM < Ki's < 4.97 nM) endowed with high selectivity over D-2, D-4, 5-HTA, and alpha(1) receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)piperazin-1-yllbutyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yllbutyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron emission tomography (PET) because of their affinity values, lipophilicity properties, and liability of C-11 labeling in the O-methyl position.