In Vivo Characterization of 5-HT7 Modulators in Rat Models of Cocaine Use Disorder

可卡因使用障碍大鼠模型中 5-HT7 调节剂的体内表征

• 批准号: 10829716
• 负责人: Benjamin Blass
• 金额: $ 125万
• 依托单位: PRAEVENTIX, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10829716
• 关键词: Vivo; Characterization; HT7; Modulators; Rat

Cocaine is one of the most commonly abused illicit drugs, and the negative impact of this drug is apparent in the 2011 Drug Abuse Warning Network (DAWN) report which revealed that >500,000 patients required hospital emergency department services as a result of cocaine use. Despite the clear and compelling need, there are no FDA approved medications for the treatment of cocaine use disorder (CUD). Cocaine produces euphoria via the mesocorticolimbic dopamine (MCL-DA) system, also known as the reward system. Dopamine release and transport systems within the MCL-DA are altered by both acute and chronic exposure to cocaine. Over time and continued use, cocaine will produce adaptations in additional neural circuits resulting in impaired executive function and decision-making processes and causing negative emotional affect for users. It has been previously demonstrated that there is substantial interplay between MCL-DA activity and serotonergic neurons that extend into this region of the brain. In addition, several studies have demonstrated that serotonin (5-HT) releasing serotonergic neurons regulate the activity of dopaminergic neurons in these regions of the MCL-DA system under both normal conditions and in the presence of cocaine. A link between DA and 5-HT7 signaling suggests that modulating 5-HT7 signaling may be a viable and novel approach to CUD. In addition to the potential of 5-HT7 antagonism to regulate the MCL-DA system, our strategy in this program stems from extensive literature demonstrating the role of 5-HT7 receptors in improving attentional set shifting, reversal learning, and extinction in preclinical assays. By improving cognitive flexibility and facilitating extinction learning in addition to modulating reward in the MCL-DA, we propose that selective 5-HT7 receptor antagonists are the pharmacotherapy strategy needed in the treatment of CUD. We have identified a series of novel, drug- like 5-HT7 receptor antagonists which reduced cocaine reinstatement in a well-established rat model of relapse in our preliminary studies. We propose to test escalating doses of our first-generation lead in this cocaine reinstatement model to achieve a full dose-response. Once achieved, we will build on our understanding of the SAR for our 5-HT7 antagonists to identify novel, orally bioavailable, BBB penetrant lead compounds optimized for advanced in vivo efficacy studies. We will test the effectiveness of our compounds to reduce ongoing cocaine responding as a potential maintenance therapeutic and to identify behaviorally active doses to be advanced for evaluation in a panel of cocaine reinstatement models including cocaine-, cue- and stress-induced reinstatement. We hypothesize that our compounds will accelerate or augment extinction learning and reduce reinstatement of cocaine responding whether produced by a noncontingent injection of cocaine, associated cues, or stress- induced by injection of yohimbine. Leads identified in these in vivo screens will move forward as preclinical candidates to use as medications to reduce the potential for relapse and improve treatment outcomes for CUD.

可卡因是最常滥用的非法药物之一，这种药物的负面影响是显而易见的 2011 年药物滥用警告网络 (DAWN) 报告显示，需要超过 500,000 名患者 因使用可卡因而获得医院急诊室服务。尽管有明确且迫切的需求， FDA 没有批准用于治疗可卡因使用障碍 (CUD) 的药物。可卡因产生 通过中皮质边缘多巴胺（MCL-DA）系统（也称为奖励系统）产生欣快感。多巴胺 MCL-DA 内的释放和转运系统会因急性和慢性接触可卡因而改变。 随着时间的推移和持续使用，可卡因会在额外的神经回路中产生适应，从而导致受损 执行功能和决策过程并对用户造成负面情绪影响。它一直 先前证明 MCL-DA 活性和血清素能神经元之间存在显着的相互作用 延伸到大脑的这个区域。此外，多项研究表明，血清素 (5-HT) 释放血清素能神经元调节 MCL-DA 这些区域中多巴胺能神经元的活动 系统在正常条件下和可卡因存在下。 DA 和 5-HT7 信号之间的联系 表明调节 5-HT7 信号传导可能是一种可行且新颖的 CUD 方法。 除了 5-HT7 拮抗作用调节 MCL-DA 系统的潜力外，我们在该计划中的策略 源于大量文献证明 5-HT7 受体在改善注意力转移方面的作用， 临床前测定中的逆转学习和消退。通过提高认知灵活性和促进灭绝 除了调节 MCL-DA 中的奖励之外，我们还建议选择性 5-HT7 受体拮抗剂 是治疗 CUD 所需的药物治疗策略。我们已经确定了一系列新颖的药物 与 5-HT7 受体拮抗剂一样，可在成熟的大鼠复发模型中减少可卡因恢复 在我们的初步研究中。我们建议测试可卡因中第一代铅的剂量递增 恢复模型以实现完全剂量反应。一旦实现，我们将在我们对 我们的 5-HT7 拮抗剂的 SAR 可以识别新型、口服生物可利用、优化的 BBB 渗透先导化合物 用于高级体内功效研究。我们将测试我们的化合物减少持续可卡因的有效性 作为潜在的维持治疗做出反应，并确定需要提前进行的行为活性剂量 可卡因恢复模型小组的评估，包括可卡因、提示和压力诱导的恢复。 我们假设我们的化合物将加速或增强灭绝学习并减少灭绝的恢复 可卡因反应，无论是由非偶然注射可卡因、相关线索还是压力引起的 通过注射育亨宾诱导。在这些体内筛选中鉴定出的先导化合物将作为临床前研究进展 候选者用作药物以减少复发的可能性并改善 CUD 的治疗结果。