Design, synthesis and characterization of dopamine receptor 3 ligands

描述（由申请人提供）：最近的研究表明，选择性D3配体可能具有治疗药物成瘾的新药物疗法的治疗潜力。虽然最近已经报道了一些选择性D3配体，但它们中的大多数在体内的溶解度很差，无法进行评估，也无法开发成潜在的有用的治疗剂。此外，没有足够的体内功能试验来明确评估它们在D3受体上的D3配体的功能活性及其在其他多巴胺受体上的功能选择性。我们最近开发并验证了新的体内功能分析，可以很好地区分D3和D2的活性。基于我们之前发现的新型D3配体，我们设计并合成了一组有效的，选择性的D3配体。我们这个项目的长期目标是开发有效的和高选择性的D3配体治疗药物滥用。为了实现这一目标，我们组建了一个多学科团队，由在计算药物设计和药物化学、多巴胺受体生化药理学和体内行为药理学方面具有广泛专业知识的研究人员组成。具体目标如下：目标一。设计和合成新的D3配体，基于我们有前途的先导化合物，以获得高效和选择性的D3配体，在体外和体内研究中都具有良好的溶解性。目标2。在一组体外受体结合和功能分析中评估这些新的D3配体，使用表达各自多巴胺受体的天然组织和转染了五种多巴胺受体的细胞系。目标3。(a)对于从Aims 1和2中获得的高选择性D3配体，使用我们新开发和验证的体内分析表征其功能活性；b)对于几个最有希望的D3配体，评估它们作为治疗药物滥用的新疗法的治疗潜力。具有不同内在活性的强效和选择性D3配体不仅可以作为进一步阐明D3受体在药物成瘾强化机制中的作用的有力药理学工具，而且最终可能成为药物成瘾和依赖的新型药物治疗方法。

DESCRIPTION (provided by the applicant): Recent studies have suggested that selective D3 ligands may have therapeutic potential as novel pharmacotherapy for the treatment of drug addiction. Although a number of selective D3 ligands have been reported recently, most of them have very poor solubility to be evaluated in vivo and to be developed as potentially useful therapeutic agents. Furthermore, there were no adequate in vivo functional assays for unambiguous evaluation of their functional activity of D3 ligands at D3 receptors and their functional selectivity at the other dopamine receptors. We have recently developed and validated new in vivo functional assays that can nicely distinguish between the D3 and D2 activities. Based on novel D3 ligands we previously discovered, we have designed and synthesized a set of potent, selective D3 ligands. Our long- term goal of this project is to develop potent and highly selective D3 ligands for the treatment of drug abuse. To achieve this goal, we have assembled a multidisciplinary team consisting of investigators with extensive expertise in computational drug design and medicinal chemistry, biochemical pharmacology of dopamine receptors, and in vivo behavioral pharmacology. We will carry out the following specific aims: Aim 1. Design and synthesize new D3 ligands, based on our promising lead compounds toward achieving highly potent and selective D3 ligands with good solubility for both in vitro and in vivo studies. Aim 2. Evaluate these new D3 ligands in a panel of in vitro receptor binding and functional assays using both the native tissues expressing respective dopamine receptors and in cell lines transfected with each of the five dopamine receptors. Aim 3. (a) For the highly selective D3 ligands obtained from Aims 1 and 2, characterize their functional activity using our newly developed and validated in vivo assays; and b) for several of the most promising D3 ligands, evaluate their therapeutic potential as a new therapy for the treatment of drug abuse. Potent and selective D3 ligands with varying intrinsic activity not only will serve as powerful pharmacological tools to further elucidate the role of the D3 receptor in the reinforcement mechanism of drug addiction, but also may ultimately be developed as novel pharmacotherapies for drug addiction and dependence.