Low-Efficacy Dopamine D4 Receptor Partial Agonists for Cocaine Addiction

用于治疗可卡因成瘾的低效多巴胺 D4 受体部分激动剂

基本信息

批准号：
10268238
负责人：
Comfort Ahenkan Boateng
金额：
$ 22.65万
依托单位：
HIGH POINT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268238
关键词：
Address Affinity Agonist Amides Area Attenuated Behavior Behavioral Biological Brain Cocaine Cocaine Dependence Cognitive DRD4 gene Data Development Disease Dopamine Antagonists Dose Drug Addiction Drug Kinetics Experimental Designs FDA approved Food Future Goals In Vitro Lead Libraries Ligands Liver Microsomes Locomotion Measures Mediating Metabolic Modeling Molecular Mus Penetration Pharmaceutical Preparations Pharmacotherapy Piperazines Plasma Positioning Attribute Pre-Clinical Model Primates Property Protocols documentation Rattus Receptor Signaling Relapse Reporting Research Rewards Role Schedule Self Administration Signal Transduction Site Structure Testing Time Training Triazoles addiction analog attenuation base behavior test behavioral study cocaine relapse cocaine self-administration cocaine use cognitive process cognitive testing comparative efficacy design drug candidate experimental study improved in vivo innovation memory process neuropsychiatric disorder nonhuman primate novel object recognition receptor receptor function recruit response side effect small molecule tool treatment effect

项目摘要

PROJECT SUMMARY/ABSTRACT Antagonism of the dopamine D4 receptor (D4R) signaling reduces drug-taking and -seeking behaviors, but may disrupt memory and cognitive processes. We hypothesize that low-efficacy partial agonists D4R may still attenuate drug-taking and -seeking behaviors with fewer disruptive side effects, representing a superior avenue for medications development for addiction. To test this hypothesis, we have developed a library of five new, structurally diverse D4R ligands with high D4R affinity, excellent D2-like subtype selectivity, and a broad range of receptor efficacies, including a high-efficacy partial agonist (1; CAB 02-017), two low-efficacy partial agonists (2, 3; CAB 02-011, CAB 03-015), and two full antagonists (4, 5; CAB 02-005, CAB 01-019). This proposal seeks to fully characterize 1-5 in comprehensive receptor screens, which will identify any important off-target effects of each drug, and in detailed pharmacokinetic analyses, including microsomal stability studies and in vivo timecourses of rat plasma and brain drug levels. These critical analyses will allow us to better design behavioral studies to test our central hypothesis and more completely interpret the results of the behavioral tests. Finally, we will evaluate the effects of 1-5 in rat models of cocaine addiction and relapse. 1-5 will be tested for their ability to shift cocaine dose-response curves in rats trained to self-administer cocaine, and their ability to attenuate relapse-like responding in cocaine-primed reinstatement tests. Preliminary data show that full antagonist 5 attenuates cocaine self-administration. The proposed Aims will allow us to test our central hypothesis, that low- efficacy D4R partial agonism can reduce cocaine-taking and -seeking behaviors. The full receptor selectivity and pharmacokinetic characterizations will not only enhance proper experimental design of our proposed behavioral studies, but will increase the utility of these compounds as broadly available research tools. Overall, this proposal leverages extensive in vitro data, and preliminary in vivo data, in support of the innovative and significant hypothesis that low-efficacy D4R partial agonists are a novel avenue for medications development for cocaine addiction.

项目概要/摘要多巴胺 D4 受体 (D4R) 信号传导的拮抗作用会减少吸毒和寻求药物的行为，但可能扰乱记忆和认知过程。我们假设低效部分激动剂 D4R 仍可能减少吸毒和寻求药物的行为，并减少破坏性副作用，这是一种更好的途径用于成瘾药物的开发。为了检验这个假设，我们开发了一个包含五个新的库，结构多样的 D4R 配体，具有高 D4R 亲和力、出色的 D2 样亚型选择性和广泛的受体功效，包括一种高效部分激动剂（1；CAB 02-017），两种低效部分激动剂（2， 3； CAB 02-011、CAB 03-015) 和两个完全拮抗剂 (4、5；CAB 02-005、CAB 01-019)。该提案旨在在综合受体筛选中充分表征 1-5，这将识别任何重要的脱靶效应每种药物，以及详细的药代动力学分析，包括微粒体稳定性研究和体内大鼠血浆和脑药物水平的时间进程。这些批判性分析将使我们能够更好地设计行为研究来测试我们的中心假设并更完整地解释行为测试的结果。最后，我们将评估1-5对可卡因成瘾和复发大鼠模型的影响。 1-5将测试他们的能力改变经过自我注射可卡因训练的大鼠的可卡因剂量反应曲线及其减弱能力可卡因引发的恢复测试中出现类似复发的反应。初步数据显示，完全拮抗剂5 减弱可卡因的自我给药。拟议的目标将使我们能够检验我们的中心假设，即低功效 D4R 部分激动可以减少可卡因的吸食和寻求行为。完整的受体选择性和药代动力学特征不仅会增强我们提出的行为的正确实验设计研究，但将增加这些化合物作为广泛可用的研究工具的效用。总体而言，本提案利用广泛的体外数据和初步体内数据，支持创新和重大假设低效 D4R 部分激动剂是可卡因药物开发的新途径瘾。