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多巴胺受体阳性变构调节剂作为认知能力下降的实际治疗方法摘要：D1多巴胺（DA）受体（D1R）的激活是在阿尔茨海默氏病或其他疾病（例如精神分裂症和帕金森氏病）中观察到的认知下降的承诺治疗策略。 Goldman-Rakic及其同事的工作表明，在学习和记忆中最佳性能是必需的，前额叶皮层（PFC）中最佳的D1R活性水平。这导致了D1R活性在PFC和认知功能中的关系的倒立假设。在低水平的D1R信号传导（例如在否认状态下），认知功能是次数均可。在极高水平的D1R活性下，如在压力期间所观察到的，认知功能也在最低水平上。 D1R激动剂在阿尔茨海默氏病模型中表现出了有望效率的效率，以改善认知能力下降，但是正构性D1R激动剂遗传的临床责任限制了其治疗翻译。 D1R阳性变构调节剂（PAM）具有高选择性，较大的治疗窗口和降低的潜力。我们已经确定了四个与高通量筛选（HTS）的结构上不同的命中。初步的药物表征已验证了这些命中，因为D1R PAM化合物没有可测量的D1R激动剂。该提案的重点是选择性地将这些命中化合物推向治疗铅。所有四个HT命中均与已知的DA配体不同，并且它们的D1R PAM活性已重新确认。在广泛的药物研究中，已进一步表征了两种命中（硫酚和嘧啶基化合物）。两种化合物均均具有DA刺激的G蛋白 - 和-Arrestin介导的信号传导，并增加DA对D1R的亲和力。噻吩命中已被证明是一种化学工具，并允许我们识别第二个D1R变构结合位点，据我们所知，该结合位点是该脚手架所特有的。当组合进行测试时，基于噻吩和吡啶酮基于PAM的最大有效浓度在更大程度上比单独使用任何PAM更大程度地刺激了DA刺激的信号传导。这些数据很难解释，而不会引用两个D1R变构位点的存在，这些D1R变构位点独立介导了这两种不同的PAM的作用。组合实验与化合物B和DETQ重复，分别由Bristol-Myers Squibb和Eli Lilly开发的已知细胞内环2（ICL2）结合D1R PAM。添加了化合物B和DETQ，均与噻吩化学型一起添加，但与嘧啶酮化学型一起添加，进一步表明D1R至少具有两个独立的PAM结合位点。我们努力的重点是优化针对D1R中一个新颖且意外的变构现场以支持治疗铅的发展的噻吩命中脚手架。 D1R PAM的治疗潜力和迄今为止的累积证据支持了新的脚手架的进一步投资以及有希望的铅化合物的药物表征。这种系统的方法将提供最先进的工具分子来研究D1R变构位点，并提高D1R PAM的治疗效用。