Novel Dopamine D3 Receptor Ligands

新型多巴胺 D3 受体配体

• 批准号: 6830642
• 负责人: Amy Hauck Newman
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6830642
• 关键词: CHO cells; chemical structure function; cocaine; dopamine receptor; drug design /synthesis /production; ligands; methamphetamine; pharmacokinetics; receptor binding; receptor expression; transfection

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.

多巴胺被认为是与可卡因的精神刺激和强化作用有关的主要神经递质。这些发现导致了大量的努力来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。在这种追求中，多巴胺D3受体亚型最近被靶向。然而，由于缺乏高选择性的D3激动剂和拮抗剂，明确的行为研究受到阻碍。基于NGB 2904设计了一系列新的化合物，其包括先前由我们实验室和其他实验室确定的用于高亲和力和选择性D3受体结合的功能部分。在这个新的系列中的所有化合物包括2，3-二氯取代的苯基哌嗪，具有不同饱和度的四个碳连接链（丁基，反丁烯基，顺丁烯基和丁炔基）和末端芳基酰胺。这些新化合物被合成、纯化、化学表征，并在体外评估与人D2、D3或D4受体cDNA转染的HEK细胞中的结合。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显示出>100的D3/D2选择性和>1000的D3/D4选择性。在体外使用D3受体转染的CHO细胞中的有丝分裂试验的功能评价证明，这些化合物是有效的拮抗剂或部分激动剂。结构-活性关系表明，与其他连接链相比，反式丁烯基连接基提供额外的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体积庞大的芳基环系统用于保持对D3的高亲和力和选择性，同时降低亲脂性。降低最有效药物亲脂性的后一个目标是改善理化性质，从而提供比现有D3药物更有利的药代动力学/生物利用度特征。尽管一些化合物显示出对D2受体的中等至高亲和力，但没有一种化合物显示出对D4的明显亲和力。这一系列中最有效和最具选择性的化合物是以数克的数量合成的，目前正在啮齿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价。虽然这些药物的临床疗效尚未得到证实，高度选择性和有效的分子探针的发展将证明是有用的，在阐明的作用D3受体发挥可卡因和甲基苯丙胺的精神兴奋剂和增强性能。