D1 dopamine receptor positive allosteric modulators as a practical treatment for cognitive decline

D1 多巴胺受体正变构调节剂作为认知衰退的实用治疗方法

基本信息

批准号：
10482360
负责人：
Kevin J. Frankowski
金额：
$ 23.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482360
关键词：
ADME Study Affinity Agonist Allosteric Site Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Animal Testing Area Arrestins Back Binding Binding Sites Cardiac Chemicals Chemosensitization Clinical Cognition Cognitive Corpus striatum structure DRD2 gene Data Development Disease Dopamine Dopamine D1 Receptor Dopamine Receptor Drug Kinetics Ensure Evaluation Family GTP-Binding Proteins Goals Golf Impaired cognition In Vitro Investigation Lead Learning Ligands Measurable Mediating Memory Metabolic Modification Nervous system structure Neurologic Process Parkinson Disease Pathway interactions Performance Permeability Pharmaceutical Chemistry Pharmacology Pharmacology Study Physiological Play Prefrontal Cortex Property Receptor Activation Receptor Signaling Reporting Role Schizophrenia Series Signal Transduction Site Solubility Stress Testing Therapeutic Thiophenes Toxicology Translations Work analog base beta-arrestin chemical synthesis cognitive benefits cognitive function drug development experimental study functional group high throughput screening improved in vivo in vivo Model motor control neuropsychiatric disorder novel novel therapeutics physical property positive allosteric modulator receptor scaffold therapeutic development therapeutic lead compound tool treatment strategy

项目摘要

Title: D1 dopamine receptor positive allosteric modulators as a practical treatment for cognitive decline Summary: Activation of the D1 dopamine (DA) receptor (D1R) is a promising treatment strategy for the cognitive decline observed in Alzheimer’s disease or other disorders such as schizophrenia and Parkinson’s disease. Work by Goldman-Rakic and colleagues has shown that an optimum level of D1R activity in the prefrontal cortex (PFC) is required for optimum performance in learning and memory. This has led to the inverted-U hypothesis for the relationship of D1R activity in the PFC and cognitive function. At low levels of D1R signaling, such as in diseased states, cognitive function is suboptimum. At extremely high levels of D1R activity, as observed during stress, cognitive function is also at suboptimum levels. D1R agonists have shown promising efficacy in Alzheimer’s disease models for ameliorating cognitive decline, however the clinical liability inherent with orthosteric D1R agonists has limited their therapeutic translation. D1R positive allosteric modulators (PAMs) have the potential for high selectivity, larger therapeutic windows and reduced tolerance. We have identified four structurally distinct hit scaffolds from high-throughput screening (HTS). Preliminary pharmacological characterization has validated these hits as D1R PAM compounds with no measurable D1R agonism on their own. The focus of this proposal is to selectively advance these hit compounds into therapeutic leads. All four HTS hits are structurally distinct from known DA ligands and their D1R PAM activities have been reconfirmed. Two hits (thiophene- and pyrimidone-based compounds) have been further characterized in a wide range of pharmacological studies. Both compounds potentiate DA-stimulated G protein- and -arrestin-mediated signaling and increase the affinity of DA for the D1R. The thiophene hit has proven useful as a chemical tool and allowed us to identify a second D1R allosteric binding site that, to our knowledge, is unique to this scaffold. When tested in combination, maximally effective concentrations of both thiophene- and pyrimidone-based PAMs potentiate DA-stimulated signaling to a greater extent than either PAM alone. These data are difficult to explain without invoking the existence of two D1R allosteric sites that independently mediate the actions of these two different PAMs. Such combination experiments were repeated with Compound B and DETQ, known intracellular loop 2 (ICL2)-binding D1R PAMs that were developed by Bristol-Myers Squibb and Eli Lilly, respectively. Both Compound B and DETQ were additive with the thiophene chemotype, but not with the pyrimidone chemotype, further suggesting that the D1R has at least two separate PAM binding sites. A major focus of our efforts will be to optimize the thiophene hit scaffold that targets a novel and unexplored allosteric site within the D1R to facilitate the development of therapeutic leads. The therapeutic potential for D1R PAMs and the cumulative evidence to date supports further investigation of new scaffolds and the pharmacological characterization of promising lead compounds. Such a systematic approach will provide state-of-the-art tool molecules to investigate D1R allosteric sites as well as advance the therapeutic utility of D1R PAMs.

标题：D1 多巴胺受体正变构调节剂作为认知衰退的实用治疗方法摘要：Goldman-Rakic 及其同事的研究表明，激活 D1 多巴胺 (DA) 受体 (D1R) 是治疗阿尔茨海默病或其他疾病（如精神分裂症和帕金森病）认知能力下降的一种有前途的治疗策略。前额叶皮层 (PFC) 中 D1R 活动的最佳水平是学习和记忆的最佳表现所必需的，这导致了关于 PFC 和 D1R 活动之间关系的倒 U 型假设。在 D1R 信号水平较低时，例如在疾病状态下，认知功能处于次优水平，正如在压力期间观察到的那样，认知功能也处于次优水平，在阿尔茨海默病中也显示出良好的疗效。然而，正构 D1R 激动剂固有的临床责任限制了 D1R 正变构调节剂 (PAM) 的治疗转化潜力。我们通过高通量筛选 (HTS) 鉴定了四种结构不同的命中支架，已验证这些命中化合物本身没有可测量的 D1R 激动作用。建议是选择性地将这些命中化合物推进为治疗先导化合物。所有四种 HTS 化合物在结构上都与已知的 DA 配体不同，并且它们的 D1R PAM 活性已在广泛的药理学研究中得到进一步证实，这两种化合物均增强 DA 刺激的 G。蛋白质和抑制蛋白介导的信号传导并增加 DA 对 D1R 的亲和力噻吩击中已被证明是有用的化学工具，使我们能够识别第二个 D1R。据我们所知，该支架是独特的变构结合位点，当组合测试时，基于噻吩和嘧啶酮的 PAM 的最大有效浓度比单独的 PAM 更大程度地增强了 DA 刺激的信号传导。解释不援引两个 D1R 变构位点的存在，这两个变构位点独立介导这两种不同的 PAM 的作用，用化合物 B 和 DETQ（已知的细胞环 2）重复此类组合实验。分别由百时美施贵宝和礼来公司开发的 (ICL2) 结合 D1R PAM 化合物 B 和 DETQ 都与噻吩化学型相加，但不与嘧啶酮化学型相加，进一步表明 D1R 至少有两个独立的。 PAM 结合位点是我们努力的一个主要重点是优化针对 D1R 内新颖且未经探索的变构位点的噻吩命中支架，以促进开发。 D1R PAM 的治疗潜力和迄今为止积累的证据支持对新支架的进一步研究和有前途的先导化合物的药理学表征，这种系统方法将为研究 D1R 变构提供最先进的工具分子。位点并提高 D1R PAM 的治疗效用。