New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers

针对 D1-D2 异聚物的治疗可卡因成瘾的新疗法

• 批准号: 10415735
• 负责人: ANNA Waclawa SROMEK
• 金额: $ 9.69万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-02 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415735
• 关键词: New; Therapeutics; Treating; Cocaine; Addiction

PROJECT SUMMARY/ABSTRACT Cocaine abuse has reached epidemic levels in North America. By 2018, over 5.5 million Americans over the age of 12 had used cocaine within the past year, and almost 1 million meet DSM-IV criteria for addiction. Overdose related deaths have more than doubled from 2007 to 2019, reaching almost 16,000 deaths in 2019. Currently, there are no FDA approved medications available for treating cocaine use disorders. About 24% of those seeking treatment will relapse within a year following treatment. Relapse rates in abstinent patients are high, because the currently available treatment regimens do not adequately address addiction. Chronic cocaine abuse leads to lasting adaptations in the limbic, motivational, and executive areas of the brain. Glutamate homeostasis is altered, and results in changes in receptor expression in the ventral tegmental area (VTA) and changes in signaling into the VTA and prefrontal cortex (PFC); relapse is associated with enhanced glutamate transmission from the PFC and amygdala into the VTA. These lasting changes result from upregulation of short-lived CREB and sustained elevation and accumulation of FosB, especially in the nucleus accumbens. By reducing the expression of FosB in the nucleus accumbens, the lasting neurological changes associated with the addictive state can be mitigated, and cocaine addiction can be successfully treated. To date, the search for a medication that can effect this change has not been successful. One potential unexplored avenue involves targeting D1-D2 heterodimers, which are largely expressed selectively in the medium spiny neurons in the nucleus accumbens shell. Mounting evidence indicates that selectively agonizing the D1-D2 heterodimers can block upregulation of CREB and the resulting overexpression of FosB in the nucleus accumbens. Thus, this approach represents a novel route for treating cocaine abuse and relapse, and holds high potential for treating patients with CUD and keeping cocaine free patients abstinent. In order to fulfill this goal, we will first focus on the synthesis of novel heterobivalent molecules which target the D1-D2 heterodimer. Second, we will evaluate the ligands for affinity, selectivity, and agonist activity at the D1-D2 heteromer complex. The goal of this project is to develop a selective D1-D2 heterodimer agonist as a novel potential therapy for cocaine use disorders.

项目总结/摘要 可卡因滥用在北美已达到流行病的程度。到2018年，超过550万美国人 在过去的一年里，12人中有100万人使用过可卡因，近100万人符合DSM-IV成瘾标准。过量 从2007年到2019年，相关死亡人数增加了一倍多，2019年达到近16，000人。目前， 没有FDA批准的药物可用于治疗可卡因使用障碍。约24%的人寻求 治疗后一年内复发。戒断患者的复发率很高，因为 目前可用的治疗方案不足以解决成瘾问题。长期滥用可卡因导致 大脑边缘系统、动机和执行区域的持久适应。谷氨酸稳态是 改变，并导致腹侧被盖区（VTA）受体表达的变化， 信号进入VTA和前额叶皮质（PFC）;复发与谷氨酸传输增强有关 从前额叶皮层和杏仁核转移到腹侧被盖区这些持久的变化是由于短暂的CREB上调， 并持续升高和积累，特别是在丘脑核。通过减少 成瘾者的神经系统改变与成瘾性行为有关， 状态可以得到缓解，可卡因成瘾可以得到成功治疗。迄今为止，寻找一种药物 能够实现这一改变的方法并不成功。一个潜在的未探索的途径涉及针对D1-D2 异源二聚体，其主要选择性地表达于延髓核中的中型多棘神经元中 壳越来越多的证据表明，选择性激动D1-D2异源二聚体可以阻断D1-D2的上调。 CREB和由此导致的丘脑核中CREFosB的过度表达。因此，这种方法代表了一种 治疗可卡因滥用和复发的新途径，并具有治疗CUD患者的高潜力， 让没有可卡因的病人禁欲为了实现这一目标，我们将首先关注小说的合成 靶向D1-D2异二聚体的异二价分子。其次，我们将评估配体的亲和力， 选择性和对D1-D2异聚体复合物的激动剂活性。该项目的目标是开发一种选择性的 D1-D2异源二聚体激动剂作为可卡因使用障碍的新的潜在治疗。