Novel Dopamine D3 Receptor Ligands

多巴胺被认为是与精神运动兴奋剂有关的主要神经递质，并加强了许多滥用药物的作用，如可卡因、甲基苯丙胺和阿片类药物。这些发现导致了对各种多巴胺受体亚型在这些滥用药物的药理学和成瘾易感性中的作用进行深入的研究。在这一追求中，多巴胺D3R亚型一直是密集的目标。为此，我们发现了选择性很强的D3R拮抗剂和部分激动剂，其中D3R/D2R-选择剂的选择性可达1000倍。此外，这些类似物中的几个已经被进一步筛选以与受体和离子通道结合，在这些其他(OFF)靶点上没有显示出显著的结合亲和力，突出表明这些药物是迄今为止报道的一些最有效和最选择性的D3R拮抗剂和部分激动剂。最近，我们将小分子SAR与D3受体晶体结构结合起来，用类D2拮抗剂乙氯必利解决了这一问题，设计了我们最新一代的D3R选择性化合物。我们假设取代的-4-苯基哌嗪末端，被定义为主要药效团(PP)，结合在D2R和D3R的邻位结合位点(OBS)内，而吲哚酰胺末端被称为次级药效团(SP)，结合在跨膜结构域(TM)1、2和7以及EL1、EL2界面的次级结合口袋(SBP)中，这与D2R有显著不同。定点突变研究已经在EL1中发现了一个单一的氨基酸(Gly94)，它在D2和D3受体之间是不同的，对亚型的选择至关重要。这些研究为这些分子中的每个成分对D3R的结合和功能功效的贡献提供了结构基础，并为最佳D3R结合亲和力、选择性和有效性的初级和次级药效团的相对定向提供了结构基础。我们探索了许多取代的苯基哌嗪作为PP和SP与不同的杂芳酰胺。此外，我们还研究了连接链的组成和手性，分离了3-OH和3-F类似物的对映体，确定了新的用于体内研究的先导分子，并发现了连接物在D3R上对这些新配体的亲和力、有效性和功能选择性的关键作用。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了有希望的行为结果。这两种化合物在代谢上都是稳定的，并减少了羟考酮的获得，这表明它们可能对阿片类药物依赖的治疗有用，但也可能有助于防止对处方阿片类药物的上瘾。与NCATS合作，分离对映体以确定R-对映体是真异构体，并开发这些化合物和其他先导分子进行临床试验。 除了针对拮抗剂和部分激动剂的双位配体外，我们还以PD128,907和PF592,379为母体分子，专注于D3R全激动剂。我们最近发现了迄今为止对D3R选择性最强的配体之一，它强调了手性在PP和连接子中的关键作用。

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.