N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists.
N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists.
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DOI：
10.1021/jm900095y
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发表时间：
2009-04-23
影响因子：
7.3
通讯作者：
Luedtke RR
中科院分区：
文献类型：
--
作者：
Newman AH;Grundt P;Cyriac G;Deschamps JR;Taylor M;Kumar R;Ho D;Luedtke RR
在本报告中，D3受体药效团被修饰为2,3- dicl和2- och3 -苯基哌嗪类化合物，目的是提高D3受体的亲和力和选择性。这种结构-活性关系（SAR）的扩展导致了第一个对映选择性D3拮抗剂（R-和S-22）的鉴定，其中D3的对映选择性比D2更明显，并且第二个细胞外环（E2）上的结合区域可能在对映选择性和D3受体选择性中都起作用。此外，我们已经发现了一些迄今为止报道的D3选择性最强的化合物，它们对D3具有高亲和力（Ki =1 nM），对D2受体亚型具有约400倍的选择性。这些类似物中有几种对D3受体的选择性优于其他60种受体，进一步强调了它们作为体内研究工具的价值。这些先导化合物还具有适合体内探索的物理特性，因此将有助于确定D3受体在体外测试中的内在活性如何与成瘾和其他神经精神疾病动物模型中的行为相关。
In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl-and 2-OCH3-phenyl piperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (Ki =1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.
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影响因子：
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