Development of Dopamine D3 Ligands as Medications for Psychostimulant Addiction

描述(由申请人提供)：我们提议的研究的长期目标是开发治疗药物成瘾的药物。最近的研究提供了令人信服的证据，表明具有拮抗剂或部分激动剂特性的对D3亚型多巴胺受体具有高度选择性的化合物有可能被开发成治疗可卡因、甲基苯丙胺和相关精神刺激剂成瘾的药物。本文提出了一项多学科研究，涉及基于结构的合理药物设计、合成和评价，以确定和开发具有成为临床有用治疗药物的潜力的化合物。形成我们研究重点的一个主要考虑是开发新的配体和新的支架，赋予D3受体相对于其他多巴胺受体亚型的结合和功能选择性，并具有良好的物理化学和药代动力学特性，以便分布到中枢神经系统。我们最近在设计和合成多巴胺D3受体的新型配体方面所做的努力为我们提供了有希望的先导化合物，这些化合物可能会通过基于结构的药物设计工作进行优化。通过追求以下具体目标，可以实现铅的发现、铅的优化以及进一步开发的候选化合物的确定和选择：(1)通过将配体对接到多巴胺D3受体的有效同源模型的活性部位上，预测蛋白质-配体相互作用，通过对铅模板进行特定的合理修饰，设计和合成新的配体。(2)建立D2受体模型并进行比较配体对接研究，以深入了解D3和D2受体选择性的结构基础，并设计具有更高选择性的新配体。(3)通过放射配基结合分析评价合成的配体与人D3、D2、D4和D1受体的体外结合亲和力，并通过腺苷环化酶实验测定配体的功能活性和选择性；(4)评价有希望的配体通过血脑屏障和实现中枢神经系统穿透的能力，为进一步研究化合物的选择奠定基础。拟议的工作涉及一组在药物设计、合成药物化学、计算化学和生物化学以及药理学方面具有经验的研究人员，除了加强我们对配体-受体相互作用的基本了解外，还应导致发现和开发新的药理工具和药物，用于治疗药物成瘾和防止药物复发。 公共卫生相关性：对可卡因和甲基苯丙胺等兴奋剂的上瘾对大量个人的健康和福祉造成巨大影响，并给卫生保健系统带来巨大负担。最近的研究结果表明，选择性地与D3亚型多巴胺受体相互作用的化合物可能对治疗成瘾和防止吸毒复发有潜在的帮助。因此，通过拟议的研究努力发现和开发治疗可卡因、甲基苯丙胺和相关精神刺激剂成瘾的药物将对社会和公众健康产生重大有益影响。

DESCRIPTION (provided by applicant): Our long-term goal of the proposed research is to develop medications for the treatment of drug addiction. Recent research has provided convincing evidence that compounds that are highly selective for the D3 subtype of dopamine receptors with antagonist or partial agonist properties have the potential of being developed into medications for the treatment of addiction to cocaine, methamphetamine, and related psychostimulants. Proposed herein is a multidisciplinary research involving structure-based rational drug design, synthesis, and evaluations to identify and develop compounds with the potential for becoming clinically useful treatment agents. A major consideration that forms the focus of our research is the development of new ligands and novel scaffolds endowed with binding and functional selectivity for the D3 receptor over other dopamine receptor subtypes and with favorable physicochemical and pharmacokinetic properties for distribution into the central nervous system. Our recent efforts on the design and synthesis of novel ligands of the dopamine D3 receptor has provided us with promising lead compounds that could potentially be optimized through structure-based drug design efforts. The envisioned goals of lead discovery, lead optimization, and identification and selection of candidates for further development are to be achieved through the pursuit of the following specific aims: (1) Design and synthesize new ligands through specific rational modifications to the lead templates on the basis of protein-ligand interactions predicted through ligand docking into the active site of a validated and refined homology model of the dopamine D3 receptor. (2) Develop a D2 receptor model and perform comparative ligand docking studies to gain insight into the structural basis of selectivity between the D3 and D2 receptors and to design new ligands with improved selectivity. (3) Evaluate the binding affinity of the synthesized ligands in vitro against human D3, D2, D4 and D1 receptors using cells expressing each subtype of receptor through radioligand binding assays and determine the functional activity and selectivity of the ligands using adenylyl cyclase assay, and (4) Evaluate promising ligands to determine their ability to cross the blood brain barrier and achieve CNS penetration for selecting compounds for further studies. The proposed effort involving a team of researchers with experience in drug design, synthetic medicinal chemistry, computational chemistry and biochemistry and pharmacology should, in addition to enhancing our basic understanding of ligand-receptor interactions, lead to the discovery and development of new pharmacological tools and medications for the treatment of drug addiction and for prevention of relapse to drug use. PUBLIC HEALTH RELEVANCE: Addiction to stimulant drugs such as cocaine and methamphetamine has a huge impact on the health and well-being of a large number of individuals and imposes a significant burden on the health care system. Results from recent research indicate that compounds that selectively interact with the D3 subtype of dopamine receptor could potentially be useful for treatment of addiction and for prevention of relapse to drug taking. The discovery and development of medications for the treatment of addiction to cocaine, methamphetamine, and related psychostimulants through the proposed research effort will therefore have a significant beneficial impact on the society and public health.