New Therapeutics for Treating Cocaine Addiction Targeting D1-D2 Heteromers

项目摘要/摘要 可卡因滥用在北美已经达到流行的程度。到2018年，超过550万年龄以上的美国人 12人中有12人在过去一年内使用过可卡因，近100万人符合DSM-IV成瘾标准。服药过量 从2007年到2019年，相关死亡人数增加了一倍多，2019年达到近1.6万人死亡。目前， 目前还没有FDA批准的治疗可卡因使用障碍的药物。约24%的求职者 治疗将在治疗后一年内复发。禁欲患者的复发率很高，因为 目前可用的治疗方案不能充分解决成瘾问题。长期滥用可卡因导致 大脑边缘、激励和执行区域的持久适应。谷氨酸动态平衡 改变，并导致腹侧被盖区(VTA)受体表达的变化，以及 向VTA和前额叶皮质(PFC)发出信号；复发与谷氨酸传递增强有关 从PFC和杏仁核进入VTA。这些持久的变化是短暂的CREB上调的结果 FosB的持续升高和积聚，尤其是在伏隔核。通过减少 FosB在伏隔核的表达及其与成瘾相关的持续性神经改变 状态可以得到缓解，可卡因成瘾也可以成功治疗。到目前为止，寻找一种药物 能够实现这一变化的努力并未取得成功。一个潜在的未开发途径涉及瞄准d1-d2 异源二聚体，主要选择性地表达在伏核中的棘神经元 壳。越来越多的证据表明，选择性地刺激d1-d2异源二聚体可以阻止血管紧张素转换酶的上调。 CREB及由此引起的伏隔核内FosB的过表达。因此，此方法代表一种 治疗可卡因滥用和复发的新途径，并具有治疗CUD和 让戒毒患者戒除可卡因。为了实现这一目标，我们将首先关注小说的合成 靶向d1-d2杂二聚体的杂二价分子。第二，我们将评估配体的亲和力， D_1-D_2异构体复合体的选择性和激动剂活性。这个项目的目标是开发一种选择性的 D1-d2异二聚体激动剂作为治疗可卡因使用障碍的新的潜在疗法。

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.