NOVEL DOPAMINE D3 RECEPTOR LIGANDS

新型多巴胺 D3 受体配体

• 批准号: 6227906
• 负责人: Amy Hauck Newman
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6227906
• 关键词: CHO cells; alpha adrenergic receptor; amides; chemical structure function; cocaine; dopamine receptor; drug abuse; drug design /synthesis /production; drug screening /evaluation; ligands; piperazines; receptor binding; receptor expression; transfection

The elucidation of the neurochemical mechanisms underlying the reinforcing effects of cocaine has lead to targetted research on strategies for the development of pharmacological treatments for cocaine abuse and addiction. Cocaine inhibits the reuptake of the monoamine neurotransmitters dopamine, serotonin and norepinephrine into their respective neurons resulting in an increase in basal levels of these substances in their respective synapses. To date, it is the overstimulation of dopamine receptors by the endogenous neurotransmitter that has been identified as the most likely neurochemical mechanism underlying cocaines reinforcing effects. Since there are five receptor subtypes in two families of dopamine receptors namely D1 (D1 and D5) and D2 (D2, D3, D4), it is of interest to characterize the role, if any, each dopamine receptor subtype may play in the pharmacological effects of cocaine. In order to achieve these goals, highly selective and potent ligands for each receptor subtype must be developed. Recently, behavioral and neuroanatomical evidence in animal models of cocaine abuse has suggested that dopamine D3 receptors may influence the behavioral effects of cocaine. Furthermore, it has recently been demonstrated that purported D3 receptor antagonists may be able to block some of the pharmacological effects of cocaine. However, there is concern that these actions may be mediated through D2 receptors and not exclusively through D3, due to the lack of selectivity of the compounds used and the high doses need to effect behavioral actions in these animal models. As a result of these investigations we have embarked on a new study to design and prepare novel D3 dopamine receptor ligands. Based on structure-activity relationships (SAR) reported in the literature and results of screening 26 compounds from our laboratory that had structural components that were similar to those reported to be important for dopamine D3 receptor binding, we developed a design strategy for novel D3 ligands. We have synthesized 10 novel compounds that incorporated the following structural features: 1)terminal tricyclic aromatic moiety, 2)amide with 3-5 carbon chain linker, 3)aryl-substituted piperazine. All compounds were evaluated for binding in a primate D3 receptor transfected CHO cell line. In addition, all compounds were evaluated for binding in D2 and D4 transfected cell lines and for binding at noradrenergic alpha 1 receptors. The results of these initial studies demonstrated the following SAR for D3 receptors in this series of compounds. A tricyclic aryl terminus is well tolerated at D3 receptors. An amide function appears to be required and at least a 4 carbon linker gives higher affinity binding at D3 than the shorter chain links. The 2,3-dichloro- aryl substituted piperazine ring provided optimal binding affinity at D3. The most potent and selective D3 ligand in this initial series demonstrated a Ki=24 nM at D3 with a D3/D4 selectivity ratio of 50 and a D3/D2 selectivity ratio of 20. Further optimization of this series of compounds is underway with a particular focus on the carbon linking chain between the aryl termini. Functional evaluation of the most selective and potent D3 ligand will allow the determination of agonist or antagonist profile. These studies are anticipated to provide a highly selective dopamine D3 receptor subtype ligand that can be used for behavioral evaluation in animal models of cocaine abuse. Furthermore, the SAR deduced from these and other studies will provide useful structural information that can be applied to the development of molecular tools such as irreversible and/or radiolabeled ligands. These ligands will enable further characterization of the structure and function of the D3 dopamine receptor subtype. - dopamine D3 receptor subtype, cocaine, D3 primate clone CHO cells

阐明可卡因强化效应背后的神经化学机制，有助于有针对性地研究可卡因滥用和成瘾的药物治疗策略。可卡因抑制单胺类神经递质多巴胺、血清素和去甲肾上腺素进入它们各自的神经元的再摄取，导致它们各自突触中这些物质的基础水平增加。迄今为止，内源性神经递质对多巴胺受体的过度刺激已被确定为最可能的可卡因强化作用的神经化学机制。由于多巴胺受体的两个家族即D1 （D1和D5）和D2 （D2, D3, D4）中有五种受体亚型，因此表征每种多巴胺受体亚型在可卡因的药理作用中可能发挥的作用是有意义的。为了实现这些目标，必须为每个受体亚型开发高选择性和有效的配体。最近，可卡因滥用动物模型的行为和神经解剖学证据表明，多巴胺D3受体可能影响可卡因的行为效应。此外，最近有研究表明，所谓的D3受体拮抗剂可能能够阻断可卡因的一些药理作用。然而，人们担心这些作用可能是通过D2受体介导的，而不仅仅是通过D3，因为所使用的化合物缺乏选择性，而且在这些动物模型中需要高剂量才能影响行为。作为这些研究的结果，我们已经开始了一项新的研究，设计和制备新的D3多巴胺受体配体。基于文献中报道的构效关系（SAR）和我们实验室筛选的26种化合物的结果，这些化合物的结构成分与报道的对多巴胺D3受体结合重要的结构成分相似，我们开发了一种新型D3配体的设计策略。我们合成了10个具有以下结构特征的新化合物：1)末端三环芳烃部分，2)具有3-5个碳链连接的酰胺，3)芳基取代哌嗪。所有化合物都在灵长类D3受体转染的CHO细胞系中进行了结合评估。此外，还评估了所有化合物在D2和D4转染细胞系中的结合能力以及与去甲肾上腺素能α - 1受体的结合能力。这些初步研究的结果表明，在这一系列化合物中，D3受体的SAR如下。三环芳基末端在D3受体中耐受性良好。酰胺功能似乎是必需的，至少一个4碳连接体在D3上比短链连接具有更高的亲和力。2,3-二氯芳基取代哌嗪环在D3上具有最佳的结合亲和力。该系列中最有效和选择性最强的D3配体在D3处Ki=24 nM， D3/D4选择性比为50，D3/D2选择性比为20。该系列化合物的进一步优化正在进行中，特别关注芳基端之间的碳连接链。对最具选择性和最有效的D3配体的功能评估将允许确定激动剂或拮抗剂的特征。这些研究有望提供一种高度选择性的多巴胺D3受体亚型配体，可用于可卡因滥用动物模型的行为评估。此外，从这些研究和其他研究中推断出的SAR将提供有用的结构信息，可用于开发分子工具，如不可逆和/或放射性标记配体。这些配体将进一步表征D3多巴胺受体亚型的结构和功能。-多巴胺D3受体亚型，可卡因，D3灵长类克隆CHO细胞