Novel Dopamine D3 Receptor Ligands

多巴胺被认为是与可卡因的精神运动刺激和强化作用相关的主要神经递质。这些发现导致了密集的努力，以表征和阐明各种多巴胺受体亚型在这种药物滥用的药理学和滥用倾向性中的作用。在这一过程中，多巴胺D3受体亚型最近成为研究目标。然而，由于缺乏高选择性D3激动剂和拮抗剂，明确的行为研究受到阻碍。为了设计一种新的D3配体来研究这种受体系统，筛选了一系列化学上不同的化合物，这些化合物具有不同的结构特征，存在于几类著名的D3剂中，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，其中包括高亲和力和选择性D3受体结合所需的功能部分。该系列化合物包括一个芳基取代哌嗪环、变烷基链连接剂（C3-C5）和末端芳基酰胺。这些新化合物经过合成、纯化、化学表征和体外评估，在转染人D2、D3或D4受体cdna的CHO细胞中结合。D3的结合亲和度范围为Ki=1.4 ~ 1460 nM。该系列中最有效的模拟物，D3/D2选择性为64，D3/D4选择性为1300。结构-活性关系表明，2,3-二氯取代的苯哌嗪是D3上高亲和力结合所必需的，其中每个具有该取代基的化合物都比其未取代的同源物更有效。氨基芳基与苯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具有相当高的亲和力，但对D2的亲和力也很高。3碳链类似物在D3上的结合效果较弱，这一点得到了之前一系列利莫唑类似物的数据的支持，其中咔唑环系统与哌嗪环通过3碳链连接。酰胺键在氟芴基环上的位置在3位或4位似乎是最佳的。虽然一些化合物对D2受体表现出中高亲和力，但没有化合物对D4表现出明显的亲和力。这一系列中最有效和最具选择性的化合物已以多克数合成，并正在若干可卡因和甲基苯丙胺滥用动物模型中进行评价。新的配体目前正在设计和制备中，其目标是保持对D3受体的高亲和力，但改善其物理化学性质，从而提供比现有D3制剂更有利的药代动力学/生物利用度。虽然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发展将证明有助于阐明D3受体在精神运动兴奋剂和增强可卡因和甲基苯丙胺特性中的作用。

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. 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.