Novel Dopamine D3 Receptor Ligands

多巴胺被认为是一种主要的神经递质，与许多滥用药物（如可卡因、甲基苯丙胺和阿片类药物）的精神运动刺激和强化作用有关。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些滥用药物的药理学和成瘾倾向中的作用。在这种追求中，多巴胺D3R亚型已被集中靶向。为此，我们发现了选择性非常高的D3R拮抗剂和D3R/ d2r选择性达到1000倍的部分激动剂。此外，这些类似物中的一些已经进一步筛选了与受体和离子通道的结合，并且在任何其他（关闭）靶标上没有显示出显着的结合亲和力，突出表明这些药物是迄今为止报道的最有效和选择性的d3r拮抗剂和部分激动剂。我们最近将小分子SAR与D3受体晶体结构结合起来，用d2样拮抗剂eticlopride来设计我们最新一代的d3r选择性化合物。我们假设取代-4-苯基哌嗪末端，定义为一级药效团（PP），结合在D2R和d3r的正位结合位点（OBS）内，而吲哚酰胺末端被称为二级药效团（SP），结合在跨膜结构域（TMs） 1、2、7和EL1、EL2界面的二级结合袋（SBP）中，这与D2R有显著不同。定点诱变研究已经在EL1中发现了一个单独的氨基酸（Gly94），它在D2和D3受体之间是不同的，并且对亚型选择性至关重要。这些研究为这些分子中各组分对D3R结合和功能功效的贡献，以及对D3R结合亲和性、选择性和功效最佳的主、次药效团的相对取向提供了结构基础。我们已经探索了许多取代苯基哌嗪作为PP和SP与不同的杂芳酰胺。此外，我们研究了连接链的组成和手性以及3-OH和3-F类似物的分离对映体，确定了新的先导分子用于体内研究，并发现了连接体在这些新型配体在D3R的亲和力，有效性和功能选择性中的关键作用。我们已经确定了两个先导分子：VK4-116和VK4-40，它们在阿片类药物滥用的啮齿动物模型中显示出有希望的行为结果。这两种化合物代谢稳定，并减少羟考酮自我给药的获得，这表明它们可能有助于治疗阿片类药物依赖，但也可能有助于预防处方阿片类药物成瘾。与NCATS合作，分离对映体以确定r对映体为自聚体，并开发这些化合物以及其他先导分子，以进行临床试验。

Dopamine has been implicated as the primary neurotransmitter associated with the psychomotor stimulant and reinforcing effects of many drugs of abuse, such as cocaine, methamphetamine and the opioids. These findings have resulted in intensive efforts to characterize and elucidate the roles of the various dopamine receptor subtypes in the pharmacology and addiction liability of these abused drugs. In this pursuit, the dopamine D3R subtype has been intensively targeted. To this end we discovered very selective D3R antagonists and partial agonists with D3R/D2R-selectivites reaching >1000-fold. In addition, several of these analogues have been further screened for binding to receptors and ion channels and did not show significant binding affinities at any of these other (off) targets, highlighting that these agents are some of the most potent and selective D3R-antagonists and partial agonists reported to date. We have more recently combined small molecule SAR with the D3 receptor crystal structure solved with the D2-like antagonist eticlopride to design our newest generation of D3R-selective compounds. We hypothesized that the substituted-4-phenylpiperazine terminus, defined as the primary pharmacophore (PP), binds within the orthosteric binding site (OBS) of both the D2R and D3Rs, while the indole amide terminus termed as the secondary pharmacophore (SP), binds in a secondary binding pocket (SBP) at the interface of transmembrane domains (TMs) 1, 2, and 7 and the EL1, EL2, that significantly differ from the D2R. Site-directed mutagenesis studies have identified a single amino acid (Gly94) in the EL1 that differs between D2 and D3 receptors and is critically important for subtype selectivity. These studies have provided a structural basis for the contribution each component in these molecules to the binding and functional efficacy at D3R, and to the relative orientation of the primary and secondary pharmacophores for optimal D3R binding affinity, selectivity and efficacy. We have explored numerous substituted phenyl-piperazines as the PP as well as SP with different heteroaryl amides. Further, we have investigated the composition and chirality of the linking chain and separated enantiomers of both the 3-OH and 3-F analogues, identifying new lead molecules for investigation in vivo and also discovering the critical role of the linker in the affinity, efficacy and functional selectivity of these novel ligands at D3R. We have identified two lead molecules: VK4-116 and VK4-40, which show promising behavioral results in rodent models of opioid abuse. Both compounds are metabolically stable and reduce acquisition to oxycodone self-administration suggesting that they might be useful as treatments for opioid dependence, but also may be useful in preventing addiction to prescription opioids. Separation of enantiomers to identify the R-enantiomer as the eutomer and development of these compounds as well as other lead molecules is underway toward clinical trials, in collaboration with NCATS. In addition to bitopic ligands directed toward antagonists and partial agonists, we have also focused on D3R full agonists, using PD128,907 and PF592,379 as parent molecules. We have recently discovered one of the most D3R-selective ligands to date which emphasized the critical role of chirality in both the PP and linker.