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

• 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
• 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

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.

项目总结/摘要 多巴胺D4受体（D4 R）信号传导的拮抗作用减少了药物服用和寻求行为，但可能 扰乱记忆和认知过程我们假设低效的部分激动剂D4 R可能仍然 减少吸毒和寻求毒品的行为，减少破坏性的副作用，是一种上级途径 用于治疗成瘾的药物开发。为了验证这一假设，我们开发了一个包含五个新的， 结构多样的D4 R配体，具有高D4 R亲和力、优异的D2样亚型选择性和广泛的 受体功效，包括高效部分激动剂（1; CAB 02-017），两种低效部分激动剂（2， 3; CAB 02-011，CAB 03-015）和两种完全拮抗剂（4，5; CAB 02-005，CAB 01-019）。这项建议旨在 在全面的受体筛选中充分表征1-5，这将确定任何重要的脱靶效应， 每种药物，并在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过程。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，并更全面地解释行为测试的结果。最后， 我们将评估1-5在可卡因成瘾和复发的大鼠模型中的作用。1-5将测试他们的能力 改变训练自我施用可卡因的大鼠的可卡因剂量反应曲线， 可卡因诱发的复吸试验中的复发样反应。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- D4 R部分激动可减少可卡因服用和寻求行为。完整的受体选择性和 药代动力学表征不仅将增强我们提出的行为的适当的实验设计， 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。总的来说，这项提案 利用广泛的体外数据和初步的体内数据，支持创新和重要的 低功效D4 R部分激动剂是可卡因药物开发的新途径的假设 成瘾