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: 10483526
• 负责人: Benjamin Blass
• 金额: $ 32万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483526
• 关键词: ABCB1 gene; Accident and Emergency department; Acute; Affect; Age; Attention; Behavioral; Binding; Binding Proteins; Biological Assay; Brain; Brain region; Chronic; Cocaine; Cocaine use disorder; Cognitive; Cues; Decision Making; Dopamine; Dose; Drug Kinetics; Drug abuse; Drug usage; Effectiveness; Electrophysiology (science); Emotional; Euphoria; Evaluation; Executive Dysfunction; Exhibits; Extinction (Psychology); FDA approved; Female; Generations; Health; Hepatocyte; Hospitals; Human; Illicit Drugs; In Vitro; Injections; Lactams; Lactones; Lead; Link; Literature; Maintenance; Medical; Metabolic; Modeling; Modification; Molecular; Neurons; Oral; Orthologous Gene; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma; Plasma Proteins; Process; Protocols documentation; Rat-1; Rattus; Reinforcement Schedule; Relapse; Reporting; Research; Reversal Learning; Rewards; Role; Running; STEM program; Safety; Series; Serotonin; Services; Signal Transduction; Solubility; Stress; Substance Use Disorder; Surveys; System; Testing; Therapeutic; Time; Treatment outcome; Yohimbine; addiction; analog; antagonist; base; cocaine exposure; cocaine self-administration; cocaine use; dopaminergic neuron; drug of abuse; effectiveness evaluation; effectiveness testing; efficacy evaluation; efficacy study; enantiomer; executive function; experimental study; flexibility; illicit drug use; improved; in vivo; learning extinction; male; neural circuit; novel; novel strategies; novel therapeutics; patch clamp; phase 2 study; pre-clinical; preclinical evaluation; programs; radioligand; receptor; response; reuptake; safety assessment; screening; serotonin 7 receptor; serotonin receptor; sex

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.

可卡因是最常被滥用的违禁药物之一，这种药物的负面影响显而易见 2011年药物滥用警告网络（DAWN）报告显示，超过50万名患者需要 医院急诊服务由于可卡因的使用。尽管有明确和迫切的需要， 没有FDA批准的用于治疗可卡因使用障碍（CUD）的药物。科帕卡巴纳生产 通过中皮质边缘多巴胺（MCL-DA）系统，也称为奖励系统。多巴胺 MCL-DA内的释放和运输系统通过急性和慢性暴露于可卡因而改变。 随着时间的推移和持续使用，可卡因将在额外的神经回路中产生适应性变化，导致受损的 执行功能和决策过程，并对用户造成负面情绪影响。已经 先前的研究表明，MCL-DA活性与多巴胺能神经元之间存在实质性的相互作用， 延伸到大脑的这个区域。此外，一些研究表明，血清素（5-HT） 释放多巴胺能神经元调节MCL-DA这些区域中多巴胺能神经元的活性 在正常情况下和可卡因的存在下。DA与5-HT 7信号转导的联系 提示调节5-HT 7信号传导可能是治疗CUD的一种可行的新方法。 除了5-HT 7拮抗剂调节MCL-DA系统的潜力外，我们在该项目中的策略 源于大量的文献证明了5-HT 7受体在改善注意力转移中的作用， 逆转学习和临床前测定中的消退。通过提高认知灵活性和促进灭绝 除了调节MCL-DA中的奖励外，我们还建议选择性5-HT 7受体拮抗剂 是治疗CUD所需的药物治疗策略。我们发现了一系列新的药物- 类似于5-HT 7受体拮抗剂，其在良好建立的复发大鼠模型中减少可卡因复发 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 恢复模型，以实现完全剂量反应。一旦实现，我们将在我们对 SAR为我们的5-HT 7拮抗剂，以确定新的，口服生物可利用的，BBB渗透剂铅化合物优化 用于先进的体内功效研究。我们将测试我们的化合物的有效性，以减少正在进行的可卡因 作为一种潜在的维持治疗，并确定行为活性剂量，以先进的 在一组可卡因复吸模型中进行评估，包括可卡因、线索和压力诱导的复吸。 我们假设，我们的化合物将加速或增强灭绝学习，并减少恢复。 可卡因反应，无论是由可卡因的非偶然注射、相关线索或压力产生的， 注射育亨宾引起的。在这些体内筛选中确定的电极导线将作为临床前 作为药物使用的候选人，以减少复发的可能性，并改善CUD的治疗结果。