Novel anti-cocaine D1 partial agonists

摘要 根据目前的统计数据，近100万人对可卡因上瘾或曾滥用可卡因。此外， 即使在戒毒几个月后，使用可卡因的复发率也非常高。不是 临床上有治疗可卡因成瘾的药物。 临床前研究包括我们的初步数据表明，多巴胺受体靶向策略 D1区部分激动剂有望成为抗可卡因药物开发的靶点。在这方面， 表现出选择性d1部分激动剂的化合物在可卡因自身给药中显示出有效性。 以及恢复动物的行为模式。然而，现有的选择性d1部分激动剂 从较差的药代动力学特性(包括口服生物利用度和血脑屏障透过性) 排除了他们的临床翻译。四氢原黄连素(THPB)化学型是一种新型的支架材料 用来开采选择性的D1部分激动剂。在这项提案中，我们将解决临床上有用的 通过在THPB先导化合物上进行战略性化学修饰来实现D1部分激动剂 药物动力学性质与D1部分激动剂平行优化的初步研究 药理学。 这项提议的长期目标是使用THPB框架来开发新的、生物可用的、选择性的D1 治疗可卡因成瘾的部分激动剂。我们将检验以下中心假设：“THPB 骨架可以在结构上被操纵以提供新颖的、生物可用的和选择性的D1部分激动剂 降低大鼠对可卡因的渴求的能力“。验证这一假说将涉及三个具体的目标 合成、体外测试和体内行为测试。在第一个具体目标中，我们将合成 含有铅中代谢不稳定官能团的生物等位取代物的THPB类似物 THPB、HUN4404和HUN361。具体目标2将包括评估体外ADME特性以及 通过各种成熟的分析方法研究多巴胺受体上配体的亲和力和功能活性 为了这样的目的。在目标3中，来自目标2的化合物符合规定的多巴胺受体活性标准并在体外 ADME属性将提交到体内PK屏幕。随后，选定的化合物将被 在一系列与可卡因成瘾有关的行为测试中进行了评估。自我管理与可卡因 复职。我们希望发现新的d1部分激动剂，它将在该领域作为新的变革性药物。 活体工具和实验性的反可卡因疗法。

ABSTRACT Close to a million people are addicted to or have abused cocaine according to current statistics. Moreover, there is an extremely high rate of relapse to cocaine use even after several months of abstinence. No medications are clinically available to treat cocaine addiction. Preclinical studies including our preliminary data, indicate that dopamine receptor targeting strategies that feature D1 partial agonism are promising for anti-cocaine medications development. In that regard, compounds that exhibit selective D1 partial agonism have demonstrated efficacy in cocaine self-administration and reinstatement behavioral paradigms in animals. However, the available selective D1 partial agonists suffer from poor pharmacokinetic properties (including oral bioavailability and blood-brain barrier penetrability) which precludes their clinical translation. The tetrahydroprotoberberine (THPB) chemotype is a novel scaffold from which to mine selective D1 partial agonists. In this proposal, we will solve the critical need for clinically useful D1 partial agonists by deploying strategic chemical modifications on the THPB lead compounds identified from our preliminary studies via parallel optimization of pharmacokinetic properties and D1 partial agonist pharmacologies. The long term goal of this proposal is to use the THPB framework to develop novel, bioavailable, selective D1 partial agonists for the treatment of cocaine addiction. We will test the central hypothesis that "The THPB framework may be structurally manipulated to afford novel, bioavailable and selective D1 partial agonists with the ability to reduce cocaine craving in rats ". Testing this hypothesis will engage three specific aims entailing synthesis, in vitro testing and in vivo behavioral assays. In the first specific aim, we will synthesize libraries of THPB analogues that contain bioisosteric replacements for metabolically labile functional groups in the lead THPBs, HUN4404 and HUN361. Specific Aim 2 will involve assessment of in vitro ADME properties as well as affinities and functional activities of the ligands at dopamine receptors via a variety of well-established assays for such. In Aim 3, compounds from Aim 2 that meet defined criteria for dopamine receptor activity and in vitro ADME properties will be submitted to an in vivo PK screen. Subsequently, selected compounds will be evaluated in a battery of behavioral assays relevant to cocaine addiction viz. self-administration and cocaine reinstatement. We expect to uncover novel D1 partial agonists that will be transformative in the field as novel in vivo tools and experimental anti-cocaine therapeutics.