Structure-based drug discovery for Dopamine D2 Receptor Selective Ligands

总结 神经递质多巴胺（DA）控制着许多中枢神经系统 通过大脑中的三个主要途径发挥作用，结节漏斗， 黑质纹状体和中皮质（中皮质和中脑边缘）。每一个都是 与不同的过程相关，功能障碍可能导致不同的 疾病和失调。已知有五种DA受体，D2（D2 R）是其中之一。 大脑中最丰富的DA受体，因此是一个重要的 许多中枢神经系统疾病的药理学靶点。大部分 用于治疗精神分裂症的临床有效的抗精神病药， 帕金森病，这是与中皮质边缘和 黑质纹状体途径的受体是D2 R激动剂或拮抗剂。此外，几个 人类滥用的药物（即，精神兴奋剂，如可卡因， 甲基苯丙胺）影响中脑边缘通路中的DA神经传递，由于 对奖励相关行为的影响。因此，D2 R也是一个焦点， 药物治疗药物滥用的发现， 目前没有的一类药物和成瘾性疾病 available.该方案的目标是克隆、表达和纯化活性态 稳定的D2 R，其量适合于进行初始结晶试验。到 获得活性状态稳定的蛋白质晶体，D2 R将与激动剂结合， 与纯化的G蛋白和/或稳定纳米抗体复合。这将使 我们的X射线晶体结构测定的长期目标和 发现用于物质治疗的D2 R选择性小分子配体 滥用障碍 本提案是对资助机会公告PA-16- 302：PHS 2016-02 NIH、CDC、FDA和ACF的综合征求， 小企业创新研究资助申请（母公司SBIR [R43/R44]）。

Summary The neurotransmitter dopamine (DA) controls many central nervous system functions through three major pathways in the brain, the tuberoinfundibular, the nigrostriatal and the mesocorticolimic (mesocortical and mesolimbic). Each is associated with different processes, and dysfunction can lead to varying diseases and disorders. There are five known DA receptors, D2 (D2R) is one of the most abundant DA receptors in the brain, and is thus an important pharmacological target for many central nervous system diseases. Most of the clinically efficacious antipsychotics used for the treatment of schizophrenia and Parkinson's disease, which are associated with the mesocorticolimbic and nigrostriatal pathways, are D2R agonists or antagonists. In addition, several drugs abused by humans (ie. psychostimulants such as cocaine and methamphetamine) affect DA neurotransmission in the mesolimbic pathway, due to their effects on reward-related behaviours. Therefore D2R is also a focus for the discovery of pharmacological treatments for substance abuse of a certain class of drugs and addiction disorders for which there are none currently available. The goal of this proposal is to clone, express and purify active-state stabilized D2R in quantities amenable to pursue initial crystallization trials. To obtain active-state stabilized protein crystals, D2R will be bound with agonist and complexed with purified G-protein and/or a stabilizing nanobody. This will enable our longer term goal of x-ray crystallographic structure determination and the discovery of D2R selective small molecule ligands for the treatment of substance abuse disorders. This proposal is in response to the Funding Opportunity Announcement PA-16- 302: PHS 2016-02 Omnibus Solicitation of the NIH, CDC, FDA, and ACF for Small Business Innovation Research Grant Appplications (Parent SBIR [R43/R44]).