Mapping the D2/D3 Dopamine Receptor Binding Sites

描述(由申请人提供)： 各种神经和神经精神障碍似乎是由于 多巴胺能系统紊乱。因为最近的研究表明 类DI和D4多巴胺受体选择性拮抗剂无效 抗精神病药物，D3多巴胺受体再次成为靶点 用于治疗精神分裂症的抗精神病药物。此外, 最近的研究表明，D3多巴胺受体亚型可能是一种 是药物治疗药物开发的重要目标 可用于吸食可卡因的人的康复。然而， 很难开发出选择性的D3受体化合物，这种化合物可以 用于D3多巴胺作用的实验或临床研究 神经精神障碍或药物滥用的受体亚型，因为D2和 D3多巴胺受体具有高度的氨基酸序列同源性 构成神经递质的跨膜区域 结合部位。在合作研究中，我们的实验室已经确定了一系列 结构上相关的化合物，从5到50倍的选择性 Lb与D2多巴胺受体亚型比较。所描述的实验 在这个提案中被设计用来识别D2中的氨基酸残基 和LB多巴胺受体结合位点，直接与 目前可用的LB选择性化合物。这将通过以下方式实现 制备与D2和LB多巴胺结构相关的突变型受体 受体亚型以精确定义药效团在体内的位置 神经递质结合部位。这些研究的结果将1)提供 关于我们目前的LB多巴胺受体选择性化合物如何与 气动变送器绑定状态和2)提供附加结构 有助于我们设计新化合物的信息，增加了 LB型多巴胺受体的选择性

DESCRIPTION (Provided by applicant): A variety of neurological and neuropsychiatric disorders appear to be due to disturbance of the dopaminergic system. Since recent studies indicate that Di-like and D4 dopamine receptor selective antagonists are not effective antipsychotics, there is a renewed focus on D3 dopamine receptors as a target for antipsychotic drugs used in the treatment of schizophrenia. In addition, recent studies suggest that the D3 dopamine receptor subtype might be an important target for the development of agents for pharmacotherapeutics that could be used in the rehabilitation of individuals who abuse cocaine. However, it has been difficult to develop selective D3 receptor compounds that can be used for experimental or clinical studies on the role of the D3 dopamine receptor subtype in neuropsychiatric disorders or drug abuse because the D2 and D3 dopamine receptors have a high degree of amino acid sequence homology within the transmembrane spanning regions, which construct the neutotransmitter binding site. In collaborative studies, our laboratory has identified a series of structurally related compounds that range from 5- to 50-fold selective for the LB compared to the D2 dopamine receptor subtype. The experiments described in this proposal are designed to identify the amino acid residues within the D2 and LB dopamine receptor binding sites that directly interact with the currently available LB selective compounds. This will be accomplished by preparing mutant receptors structurally related to the D2 and LB dopamine receptor subtypes to precisely define the position of the pharmacophore within the neurotranamitter binding site. The results of these studies will 1) provide information on how our current LB dopamine receptor selective compounds bind to the neumtransmitter binding sate and 2) provide additional structural information that will assist us in the design of novel compounds with increased selectivity for LB dopamine receptors