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.

项目摘要/摘要 多巴胺D4受体（D4R）信号传导的拮抗作用会降低吸毒和寻求行为，但可以 破坏记忆和认知过程。我们假设低效率的部分激动剂D4R可能仍然 减轻毒品吸毒和寻求 - 具有较少副作用的行为，代表高级途径 用于成瘾的药物开发。为了检验这一假设，我们开发了一个由五个新的库 具有高D4R亲和力的结构多样的D4R配体，出色的D2样亚型选择性和广泛的范围 受体功效，包括高效率部分激动剂（1; CAB 02-017），两个低效能的部分激动剂（2，2，， 3; CAB 02-011，CAB 03-015）和两个完整的对手（4，5; CAB 02-005，CAB 01-019）。该提议试图 在综合受体屏幕中完全表征1-5 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库。这些批判性分析将使我们能够更好地设计行为 研究我们的中心假设，并更完全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大鼠模型中的影响。 1-5将对他们的能力进行测试 在接受自动可卡因的大鼠中转移可卡因剂量响应曲线，并能够减弱它们的能力 在可卡因定位的恢复测试中反应类似复发。初步数据显示完整的拮抗剂5 减弱可卡因自我管理。拟议的目标将使我们能够检验我们的中心假设，这是低 - 功效D4R部分激动剂可以减少可卡因的造成和寻求行为。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适当实验设计 研究，但会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，该提议 利用广泛的体外数据和初步体内数据，以支持创新和重要的 假设低效率D4R部分激动剂是可卡因的药物开发途径 瘾。