Novel anti-cocaine D1 partial agonists

摘要 根据目前的统计数字，近100万人对可卡因上瘾或滥用可卡因。此外，委员会认为， 即使在戒断几个月后，可卡因的复吸率也极高。没有 临床上有治疗可卡因成瘾的药物。 包括我们的初步数据在内的临床前研究表明， 特征D1部分激动作用对于抗可卡因药物开发是有希望的。在这方面， 表现出选择性D1部分激动作用的化合物已经证明在可卡因自身给药中的功效 并在动物中恢复行为模式。然而，可获得的选择性D1部分激动剂遭受 不良的药代动力学特性（包括口服生物利用度和血脑屏障穿透性）， 排除了它们的临床转化。四氢原小檗碱（THPB）化学型是一种新的支架， 其用于开采选择性D1部分激动剂。在这项提案中，我们将解决临床上有用的 D1部分激动剂，通过对THPB先导化合物进行战略化学修饰， 我们的初步研究通过平行优化的药代动力学特性和D1部分激动剂 药理学 本提案的长期目标是使用THPB框架开发新的、生物可利用的、选择性D1 用于治疗可卡因成瘾的部分激动剂。我们将测试中心假设，“THPB 可以在结构上操纵骨架以提供新的、生物可利用的和选择性的D1部分激动剂， 减少老鼠对可卡因的渴望的能力“。测试这一假设将涉及三个具体目标， 合成、体外测试和体内行为测定。在第一个具体目标中，我们将合成 THPB类似物，其包含先导化合物中代谢不稳定官能团的生物电子等排替代物 THPB，HUN4404和HUN361。具体目标2将涉及评估体外ADME特性以及 通过各种成熟的测定， 对于这样的。在目标3中，来自目标2的化合物满足多巴胺受体活性的定义标准，并且在体外 将提交ADME特性进行体内PK筛选。随后，将选择化合物 在一系列与可卡因成瘾相关的行为测定中进行评价，即自我给药和可卡因 复职我们希望发现新的D1部分激动剂，这将是该领域的变革， 体内工具和实验性抗可卡因疗法。

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.