Novel Dopamine D3 Receptor Ligands

多巴胺被认为是与精神运动兴奋剂和可卡因的强化作用有关的主要神经递质。这些发现导致了对各种多巴胺受体亚型在这种滥用药物的药理学和滥用易感性中的作用进行深入的研究。在这一追求中，多巴胺D3受体亚型最近成为了目标。然而，由于缺乏高选择性的D3激动剂和拮抗剂，决定性的行为研究一直受到阻碍。基于NGB 2904设计了一系列新的化合物，包括我们实验室和其他实验室先前确定的高亲和力和选择性D3受体结合的功能部分。这个新系列的所有化合物都包括一个2，3-二氯取代的苯基哌嗪，一个不同饱和度的四碳连接链(丁基、反丁烯基、顺丁烯基和丁烯基)和一个末端芳香酰胺。这些新化合物被合成、纯化、化学表征，并在体外与转染人D2、D3或D4受体cDNA的HEK细胞结合。D3结合亲和力为KI=0.5-500 nm。该系列中最有效的类似物显示了&gt；100的D3/D2选择性和&gt；1000的D3/D4选择性。体外有丝分裂实验表明，这些化合物既是有效的拮抗剂，也是部分激动剂。结构-活性关系表明，与其他连接链相比，反丁烯基链提供了额外的D3选择性。此外，与母体化合物NGB 2904和MJR2-7相比，用各种杂芳基取代空间大的芳基体系有助于保持对D3的高亲和力和选择性，同时降低亲油性。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。虽然一些化合物对D2受体表现出中等到高的亲和力，但没有一种化合物对D4表现出明显的亲和力。这一系列中最有效和最有选择性的化合物是以多克数量合成的，目前正在几种啮齿动物和灵长类动物中滥用可卡因和甲基苯丙胺的动物模型中进行评估。虽然这些药物的临床疗效尚未得到证实，但高选择性和强大的分子探针的开发将有助于阐明D3受体在精神运动兴奋剂中所起的作用，并增强可卡因和甲基苯丙胺的特性。

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.