NOVEL LIGANDS FOR STUDIES OF D3 DOPAMINE RECEPTORS

用于 D3 多巴胺受体研究的新型配体

• 批准号: 2251354
• 负责人: MEI-PING tien KUNG
• 金额: $ 12.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2251354
• 关键词: acidity /alkalinity; aging; antipsychotic agents; autoradiography; chemical kinetics; clozapine; dopamine receptor; drug administration rate /duration; drug interactions; guanine nucleotides; haloperidol; image processing; iodine; laboratory rat; ligands; neuroanatomy; neuropharmacology; phenylamide; radionuclides; radiotracer; receptor binding; receptor expression; receptor sensitivity

We propose to investigate D2 and D3 dopamine receptors using newly developed selective ligands. The information to be generated by this project is essential for the understanding of pharmacology as well as the relevance of D2 and D3 dopamine receptors on the mechanism of action of neuroleptics for treatment and management of patients with mental illness. The dopaminergic system is very important for normal brain function, and it is also a possible primary action site for various neuroleptic drugs for treatment of schizophrenia and other mental disorders. Application of molecular biology techniques in expressing dopamine receptor subtypes: D1, D2L, D2S, D3, D4 and D5, in cloned cells have been reported. Among the subtypes, the D3 receptor has been postulated as a potential target site for neuroleptics and it may mediate dopaminergic control of cognitive, emotional, and endocrine functions, extremely important mechanisms for antipsychotic actions. Regional distribution of mRNA of D3 receptors in rat brain showed predominantly high density in the limbic system, including the olfactory tubercle, nucleus accumbens, island of calleja and hypothalamus. The neuroleptics, such as haloperidol and sulpiride, showed high D3 receptor binding as well as a high degree of D2 receptor binding. Recently, [3H]7-OH-DPAT was reported as a selective D3 dopamine receptor ligand. Based on this structure we have successfully developed the first iodinated D3 dopamine ligand, [125I]Trans-7-OH-PIPAT(Trans-7-hydroxy-2- (N-n-propyl-N-3'-iodo-2'-propenyl)aminotetralin). This iodinated analog is the first novel ligand demonstrating unique high affinity and selectivity toward the D3 receptor (Kd=0.48 nM in rat striatal membrane homogenates). Preliminary autoradiography of rat brain sections showed that this new ligand displayed a regional distribution pattern consistent with that measured with mRNA hybridization. Using in vitro homogenate binding assay and autoradiography techniques, measurements of D3 receptor density, regional distribution as well as functional linkage of drug- ligand interaction of this receptor in normal and neuroleptic-treated rat brain and proposed. In addition, parallel studies of D2 dopamine receptor with [125I]FIDA2, (S)-(-)-2-Fluoroethoxy-5-iodo-3-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl] benzamide, a potent D2 dopamine receptor ligand (Kd=0.02 nM), in normal and treated rats will also be performed. Due to the high binding affinity (in nM) of endogenous dopamine to the D3 dopamine receptor, it is known that D3 receptors are mostly saturated in normal states. If the lack of, or the depressed level of endogenous dopamine is the key event which precipitates the neurological diseases, then D3 ligands may potentially provide a very useful tool to clearly define the role of the dopaminergic system in these diseases.

我们建议使用新的D2和D3多巴胺受体研究 开发的选择性配体。要生成的信息 项目对于理解药理学以及 D2和D3多巴胺受体与作用机理的相关性 用于治疗和管理精神患者的神经益生类 疾病。 多巴胺能系统对于正常的大脑功能非常重要，并且 它也是各种神经饱和药物的主要动作部位 用于治疗精神分裂症和其他精神障碍。应用 表达多巴胺受体亚型的分子生物学技术： 已经报道了克隆细胞中的D1，D2L，D2S，D3，D4和D5。之中 亚型，D3受体已被假定为潜在目标 神经摄影的部位，它可能介导多巴胺能控制 认知，情感和内分泌功能，极为重要 抗精神病药的机制。 mRNA的区域分布 大鼠脑中的D3受体在边缘表现出高度高密度 系统，包括嗅觉结节，伏隔核，岛 Calleja和下丘脑。神经摄影，例如氟哌啶醇和 硫酸盐，表现出高D3受体结合以及高度的 D2受体结合。 最近，据报道[3H] 7-OH-DPAT作为选择性D3多巴胺受体 配体。基于这种结构，我们成功地开发了第一个 碘化的D3多巴胺配体，[125i] trans-7-OH-Pipat（trans-7-Hydroxy-2- （N-N-N-popyl-n-3'-iodo-2'-丙烯基）氨基丁素）。这个碘化的类似物 是第一个新颖的配体，展示了独特的高亲和力和 对D3受体的选择性（大鼠纹状体膜中的KD = 0.48 nm 匀浆）。大鼠脑切片的初步放射自显影显示 这种新配体显示了区域分布模式一致的 用mRNA杂交测量。使用体外匀浆 结合测定和放射自显影技术，D3受体的测量值 密度，区域分布以及药物的功能连锁 该受体在正常和神经治疗的大鼠中的配体相互作用 大脑和提议。另外，D2多巴胺受体的平行研究 与[125i] fida2，（s） - （ - ） - 2-氟乙氧基-5- ioodo-3-甲氧基-N- [（1-乙基-2-- 吡咯胺）甲基]苯甲酰胺，一种有效的D2多巴胺受体配体 （Kd = 0.02 nm），在正常和处理的大鼠中也将进行。 由于内源性多巴胺的结合亲和力高（以NM为单位） D3多巴胺受体，已知D3受体大多饱和 在正常状态。如果缺乏内源性或抑郁水平 多巴胺是沉淀神经系统疾病的关键事件， 那么D3配体可能会提供一个非常有用的工具来清楚 定义多巴胺能系统在这些疾病中的作用。