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.

可卡因是最常见的滥用非法药物之一，这种药物的负面影响显而易见 在2011年的药物滥用警告网络（DAWN）报告中，该报告显示需要> 500,000名患者 可卡因使用的医院急诊科服务。尽管需要明确和迫切的需求 没有FDA批准的可卡因使用障碍（CUD）药物。可卡因产生 通过中皮质糖多巴胺（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会因可卡因急性和慢性暴露而改变。 随着时间的流逝和继续使用，可卡因将在其他神经回路中产生适应性 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活性与5-羟色源性神经元之间存在实质性相互作用 延伸到大脑的这个区域。此外，几项研究表明5-羟色胺（5-HT） 释放血清素能神经元调节在MCL-DA的这些区域中多巴胺能神经元的活性 在正常条件下和可卡因存在下的系统。 DA和5-HT7信号之间的链接 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拮抗剂调节MCL-DA系统的潜力外，我们在该程序中的策略 源自广泛的文献，证明了5-HT7受体在改善注意力集转移中的作用， 逆转学习和临床前测定中的灭绝。通过提高认知灵活性并促进灭绝 除了调节MCL-DA的奖励外，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 - 像5-HT7受体拮抗剂，在良好的大鼠复发模型中减少了可卡因的恢复原状 在我们的初步研究中。我们建议在此可卡因中测试我们第一代铅的升级剂量 恢复模型以实现完整的剂量反应。一旦实现，我们将基于我们对 SAR为我们的5-HT7拮抗剂识别出了新颖的，可生物利用的BBB渗透铅化合物的SAR 用于先进的体内功效研究。我们将测试化合物的有效性以减少可卡因 作为一种潜在的维护治疗，并确定以行为活跃的剂量要进行的 在包括可卡因，提示和应力诱导的恢复的一组可卡因恢复模型中评估。 我们假设我们的化合物将加速或增加灭绝学习，并减少恢复的 可卡因反应可卡因，相关线索或应力 - 通过注射Yohimbine诱导。在这些体内屏幕中鉴定出的铅将作为临床前向前移动 候选人用作药物，以减少复发的潜力并改善CUD的治疗结果。