Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands:: Inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors
Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands:: Inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors
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DOI：
10.1021/jm0211220
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发表时间：
2003-08-28
影响因子：
7.3
通讯作者：
Mennini, T
中科院分区：
文献类型：
--
作者：
Campiani, G;Butini, S;Mennini, T
本文描述了一系列与BP897结构相关的新型芳基烷基哌嗪的合成、药理评价和构效关系（sar）(3)。在结合研究中，新的衍生物对一组多巴胺、血清素和去甲肾上腺素受体亚型进行了测试。SAR研究主要关注多巴胺D-3受体，揭示了高受体亲和力和选择性所需的一些结构特征。研究人员探索了几种杂芳烃系统对多巴胺受体的亲和力，并结合合成、生物学和分子模型，确定了开发有效和选择性D-3受体配体的新结构线索。引入吲哚环连接到二氯苯基哌嗪系统，提供了迄今为止已知的两种最有效和选择性的配体（在皮摩尔范围内的D-3受体亲和力）。[S-35]-GTPgammaS结合试验还评估了一组强效D-3受体配体的内在药理学特性。特别是来自动物研究的证据，强调了多巴胺能系统在环境刺激如何诱导药物寻求行为中的作用。因此，我们在体内测试了两种新型的D-3受体部分激动剂和一种强效的D-3选择性拮抗剂，以观察它们对在长期戒断后重新引入可卡因相关刺激而诱导的可卡因寻求行为的影响，并且不再使用可卡因。化合物5g是一种非选择性的部分D-3受体激动剂，其药理特征与3相似，而5p是一种强效的选择性D-3拮抗剂，可减少由可卡因相关刺激重新引入引起的活性杠杆压力的数量。然而，5q，一种高效和选择性的D-3部分激动剂，对可卡因寻求行为没有任何影响。尽管需要进行脑摄取研究来确定这些化合物是否能达到与体外活性D-3受体相当的脑浓度，但我们的实验表明，D-2受体的拮抗作用可能显著有助于部分D-3激动剂减少对可卡因的渴望。
The synthesis, pharmacological evaluation, and structure activity relationships (SARs) of a series of novel arylalkylpiperazines structurally related to BP897 (3) are described. In binding studies, the new derivatives were tested against a panel of dopamine, serotonin, and noradrenaline receptor subtypes. Focusing mainly on dopamine D-3 receptors, SAR studies brought to light a number of structural features required for high receptor affinity and selectivity. Several heteroaromatic systems were explored for their dopamine receptor affinities, and combinations of synthesis, biology, and molecular modeling, were used to identify novel structural leads for the development of potent and selective D-3 receptor ligands. Introduction of an indole ring linked to a dichlorophenylpiperazine system provided two of the most potent and selective ligands known to date (D-3 receptor affinity in the picomolar range). The intrinsic pharmacological properties of a subset of potent D-3 receptor ligands were also assessed in [S-35]-GTPgammaS binding assays. Evidence from animal studies, in particular, has highlighted the dopaminergic system's role in how environmental stimuli induce drug-seeking behavior. We therefore tested two novel D-3 receptor partial agonists and a potent D-3-selective antagonist in vivo for their effect in the cocaine-seeking behavior induced by reintroduction of cocaine-associated stimuli after a long period of abstinence, and without any further cocaine. Compound 5g, a nonselective partial D-3 receptor agonist with a pharmacological profile similar to 3, and 5p, a potent and selective D-3 antagonist, reduced the number of active lever presses induced by reintroduction of cocaine-associated stimuli. However, 5q, a highly potent and selective D-3 partial agonist, did not have any effect on cocaine-seeking behavior. Although brain uptake studies are needed to establish whether the compounds achieve brain concentrations comparable to those active in vitro on the D-3 receptor, our experiments suggest that antagonism at D-2 receptors might significantly contribute to the reduction of cocaine craving by partial D-3 agonists.