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

对可卡因强化作用的神经化学机制的阐明导致了对开发可卡因滥用和成瘾药物治疗策略的有针对性的研究。辅酶A抑制单胺神经递质多巴胺、5-羟色胺和去甲肾上腺素再摄取到它们各自的神经元中，导致这些物质在它们各自的突触中的基础水平增加。到目前为止，内源性神经递质对多巴胺受体的过度刺激已被确定为可卡因强化作用的最可能的神经化学机制。由于在多巴胺受体的两个家族中存在五种受体亚型，即D1（D1和D5）和D2（D2、D3、D4），因此有兴趣表征每种多巴胺受体亚型在可卡因的药理学作用中可能发挥的作用（如果有的话）。为了实现这些目标，必须开发针对每种受体亚型的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受体可能会影响可卡因的行为效应。此外，最近已经证明，声称的D3受体拮抗剂可能能够阻断可卡因的一些药理学作用。然而，人们担心这些作用可能通过D2受体介导，而不仅仅是通过D3介导，因为所用化合物缺乏选择性，并且需要高剂量才能在这些动物模型中实现行为作用。作为这些调查的结果，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。基于文献中报道的结构-活性关系（SAR）和从我们实验室筛选的26种化合物的结果，这些化合物具有与报道的对多巴胺D3受体结合重要的结构组分相似的结构组分，我们开发了一种新型D3配体的设计策略。我们合成了10个新的化合物，它们具有以下结构特征：1）末端三环芳香基团，2）3-5碳链连接的酰胺，3）芳基取代的哌嗪。评价所有化合物在灵长类动物D3受体转染的CHO细胞系中的结合。此外，评价了所有化合物在D2和D4转染细胞系中的结合以及在去甲肾上腺素能α 1受体上的结合。这些初步研究的结果证明了该系列化合物中D3受体的以下SAR。三环芳基末端在D3受体处耐受良好。似乎需要酰胺官能团，并且至少4个碳的接头在D3处比较短的链连接提供更高的亲和力结合。2，3-二氯-芳基取代的哌嗪环在D3处提供最佳结合亲和力。该初始系列中最有效和选择性的D3配体在D3处显示Ki=24 nM，D3/D4选择性比为50，D3/D2选择性比为20。这一系列化合物的进一步优化正在进行中，特别关注芳基末端之间的碳连接链。最具选择性和有效的D3配体的功能评价将允许确定激动剂或拮抗剂特征。这些研究有望提供一种高选择性的多巴胺D3受体亚型配体，可用于可卡因滥用动物模型的行为评价。此外，从这些和其他研究推导出的SAR将提供有用的结构信息，可以应用于分子工具的开发，如不可逆的和/或放射性标记的配体。这些配体将能够进一步表征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克隆CHO细胞