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。为了设计一类新的D3配体来研究这一受体系统，我们筛选了一系列具有不同结构特征的化合物，这些化合物存在于几类著名的D3药物中，并与最近报道的D3拮抗剂NGB 2904进行了比较。基于这些结果，设计了一系列新的化合物，包括高亲和力和选择性结合D3受体所需的功能部分。这一系列的所有化合物都包括芳基取代的哌嗪环、不同的烷基链连接物(C3-C5)和末端的芳基酰胺。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CHO细胞结合。D3结合亲和力为KI=1.4-1460 nm。本系列中最有效的类似物显示，D3/D2的选择性为，D3/D4的选择性为1300。构效关系表明，2，3-二氯取代的苯基哌嗪在D3时需要高亲和力的结合，其中每个具有该取代基的化合物都比其未取代的同系物更有效。在氨基-芳基和苯基哌嗪之间的最佳烷基链长为4个碳。虽然5碳连接的化合物对D3表现出相当高的亲和力，但D2亲和力也很高。3-碳链类似物在D3时结合能力较弱，这得到了一系列利咪唑类似物以前获得的数据的支持，其中咔唑环系通过3-碳链连接到哌嗪环上。荧环上的酰胺键的位置似乎在3-或4-位是最佳的。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，并正在几种可卡因和甲基苯丙胺滥用的动物模型中进行评估。现在已经设计并正在制备新的配体，目标是保持对D3受体的高亲和力，但改善物理化学性质，提供比现有D3试剂更有利的药代动力学/生物利用度曲线。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. In an attempt to design a novel class of D3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D3 agents was screened and compared to the recently reported D3 antagonist, NGB 2904. Based on these results, a novel series of compounds was designed that included functional moieties that were required for high affinity and selective D3 receptor binding. All the compounds in this series included an aryl-substituted piperazine ring, varying alkyl chain linker (C3-C5) and a terminal aryl amide. These novel compounds were synthesized, purified, chemically characterized and evaluated in vitro for binding in CHO cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from Ki=1.4-1460 nM. The most potent analog in this series, demonstrated a D3/D2 selectivity of 64 and a D3/D4 selectivity of 1300. Structure-activity relationships demonstrated that the 2,3-dichloro-substituted phenylpiperazine was required for high affinity binding at D3, wherein every compound with this substituent was more potent than its unsubstituted homologue. The optimum alkyl chain length, between the amido-aryl function and the phenylpiperazine was four carbons. Although the 5-carbon linked compounds exhibited reasonably high affinity for D3, D2 affinity was also very high. The 3-carbon chained analogs resulted in less potent binding at D3, which was supported by previously obtained data with a series of rimcazole analogs, wherein the carbazole ring system was linked to the piperazine ring with a 3-carbon chain. The position of the amide-linkage on the fluorenyl ring appears to be optimal at either the 3- or 4-positions. 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 compound, of this series, has been synthesized in multigram quantities and is being evaluated in several animal models of cocaine and methamphetamine abuse. Novel ligands have now been designed and are currently being prepared with the goal of retaining high affinity for D3 receptors, but improving physico-chemical properties that will provide a more favorable pharmacokinetic/bioavailability profile than the currently existing D3 agents. 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.