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（mesocorticolimic）（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 中枢神经系统（CNS）的疾病和病症。有五 已知的DA受体中，D2（D2 R）是多巴胺受体中最丰富的DA受体之一。 脑，因此是许多CNS疾病的重要药理学靶点。 大多数临床上有效的抗精神病药物用于治疗 精神分裂症和帕金森氏病，这与 中皮质边缘和黑质纹状体途径是D2 R激动剂或拮抗剂。 然而，需要具有改善的功效和副作用特征的新药 这些相对流行的疾病。此外，一些药物滥用， 人类影响中脑边缘通路中的DA神经传递，这是由于他们的 对奖励相关行为的影响因此，D2 R也是 发现了某种药物滥用的药物治疗方法 药物和成瘾性疾病，目前还没有。的 本计划的目标是发现新的D2 R选择性小分子配体 其可以被开发用于治疗CNS病症。利用 D2 R三维结构的组合，包括活性态 在我们的第一阶段研究中获得的结构，虚拟筛选和DNA- 编码库筛选，我们将确定和开发新的先导化合物。 这些D2 R靶向化合物将被优化并进行临床前研究。 在这一点上，我们将寻求商业合作， 制药公司。 本提案是对资助机会公告PA-18- 574，“PHS 2018-02 NIH，CDC和FDA的小型 商业创新研究资助申请（母公司SBIR [R43/R44]） 不允许进行临床试验）"。

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 of the central nervous system (CNS). 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 CNS 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. However, new drugs with improved efficacy and side-effect profiles are needed for these relatively prevalent diseases. In addition, several drugs abused by humans affect DA neurotransmission in the mesolimbic pathway, due to their effects on reward-related behaviors. 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 discover novel D2R selective small molecule ligands that can be developed for the treatment of disorders of the CNS. Utilizing a combination of D2R three-dimensional structures, including the active-state structure obtained during our Phase I studies, virtual screening and DNA- encoded library screening, we will identify and develop novel lead compounds. These D2R targeted compounds will be optimized and undergo pre-clinical studies at which point we will seek commercial collaboration with a large pharmaceutical company. This proposal is in response to the Funding Opportunity Announcement PA-18- 574, “PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)”.