Novel Dopamine D3 Receptor Ligands

多巴胺被认为是与可卡因的精神运动兴奋剂和增强作用相关的主要神经递质。这些发现导致人们大力努力表征和阐明各种多巴胺受体亚型在这种滥用药物的药理学和滥用倾向中的作用。在这一追求中，多巴胺 D3 受体亚型最近成为了目标。然而，由于缺乏高度选择性的 D3 激动剂和拮抗剂，最终的行为研究受到了阻碍。基于 NGB 2904 设计了一系列新颖的化合物，其中包括我们实验室和其他实验室之前确定的具有高亲和力和选择性 D3 受体结合的功能部分。该新系列中的所有化合物均包含 2,3-二氯取代的苯基哌嗪、具有不同饱和度的四碳连接链（丁基、反式丁烯基、顺式丁烯基和丁炔基）和末端芳基酰胺。这些新化合物经过合成、纯化、化学表征并在体外评估其在转染人 D2、D3 或 D4 受体 cDNA 的 HEK 细胞中的结合情况。 D3 结合亲和力范围为 Ki=0.5-500 nM。该系列中最有效的类似物表现出 >100 的 D3/D2 选择性和 >1000 的 D3/D4 选择性。在 D3 受体转染的 CHO 细胞中使用有丝分裂测定进行的体外功能评估表明，这些化合物要么是有效的拮抗剂，要么是部分激动剂。结构-活性关系表明，与其他连接链相比，反式丁烯基连接体提供了额外的 D3 选择性。此外，与母体化合物 NGB 2904 和 MJR 2-7 相比，用各种杂芳基取代空间庞大的芳基环系统可以保留对 D3 的高亲和力和选择性，同时降低亲脂性。降低最有效药物的亲脂性的后一个目标是改善物理化学性质，这将提供比目前现有的 D3 药物更有利的药代动力学/生物利用度特征。尽管一些化合物对 D2 受体表现出中等至高的亲和力，但没有一种化合物对 D4 表现出明显的亲和力。该系列中最有效和最具选择性的化合物以数克数量合成，目前正在啮齿类动物和灵长类动物的几种可卡因和甲基苯丙胺滥用动物模型中进行评估。尽管这些药物的临床疗效尚未得到证实，但高选择性和有效的分子探针的开发将有助于阐明 D3 受体在可卡因和甲基苯丙胺的精神运动兴奋剂和增强特性中所起的作用。

Dopamine has been implicated as the primary neurotransmitter associated with the psychomotor stimulant and reinforcing effects of cocaine. These findings have resulted in intensive efforts to characterize and elucidate the roles of the various dopamine receptor subtypes in the pharmacology and abuse liability of this drug of abuse. In this pursuit, the dopamine D3 receptor subtype has been recently targeted. However, definitive behavioral investigations have been hampered by the lack of highly selective D3 agonists and antagonists. A novel series of compounds was designed, based on NGB 2904, that included functional moieties that were previously determined by our laboratory and others for high affinity and selective D3 receptor binding. All the compounds in this novel series included a 2,3-dichloro-substituted phenylpiperazine, a four carbon linking chain with varying saturation (butyl, trans butenyl, cis-butenyl and butynyl) and a terminal aryl amide. These novel compounds were synthesized, purified, chemically characterized and evaluated in vitro for binding in HEK cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from Ki=0.5-500 nM. The most potent analogs in this series, demonstrated D3/D2 selectivity of >100 and a D3/D4 selectivity of >1000. Functional evaluation in vitro using a mitogenesis assay in D3 receptor transfected CHO cells demonstrated that these compounds were either potent antagonists or partial agonists. Structure-activity relationships demonstrated that trans-butenyl linker provided additional D3 selectivity as compared to the other linking chains. Further, replacement of the sterically bulky aryl ring system with various heteroaryl groups served to retain high affinity and selectivity for D3, while decreasing lipophilicity, as compared to the parent compound NGB 2904 and MJR 2-7. The latter goal of reducing lipophilicity of the most potent agents was to improve physico-chemical properties that would provide a more favorable pharmacokinetic/bioavailability profile than the currently existing D3 agents. Although some of the compounds displayed moderate to high affinity for D2 receptors, none of the compounds displayed appreciable affinity for D4. The most potent and selective compounds, of this series, were synthesized in multigram quantities and are currently being evaluated in several animal models of cocaine and methamphetamine abuse, in both rodents and primates. Although clinical efficacy of these agents has yet to be substantiated, the development of highly selective and potent molecular probes will prove useful in the elucidation of the role D3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine and methamphetamine.