KCa2 Channel Activators for Opioid Use Disorder

用于治疗阿片类药物使用障碍的 KCa2 ​​通道激活剂

• 批准号: 10511349
• 负责人: HEIKE WULFF
• 金额: $ 41.99万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511349
• 关键词: Abstinence; Acute Pain; Address; Affect; Affinity; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; American; Apamin; Behavior; Binding; Brain; Brain region; Calcium-Activated Potassium Channel; Calmodulin; Cessation of life; Chemicals; Classification; Clinical; Cryoelectron Microscopy; Crystallization; Data; Development; Disease; Docking; Drug Design; Drug usage; Electrophysiology (science); Experimental Models; FDA approved; Funding Opportunities; Goals; Helping to End Addiction Long-term; Homology Modeling; Human; Individual; Injections; Ion Channel; Laboratories; Length; Libraries; Ligands; Machine Learning; Methods; Modeling; Modification; Molecular; Morphine Dependence; Mus; Mutagenesis; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Overdose; Pain; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Play; Post-Traumatic Stress Disorders; Prevention; Publishing; Rattus; Rodent; Rodent Model; Role; Running; Structure; Substance Addiction; Substance Use Disorder; Techniques; Testing; Therapeutic; Therapeutic Agents; Validation; Ventilatory Depression; alcohol seeking behavior; base; benzothiazole; chronic pain; comorbidity; convolutional neural network; craving; design; experience; high throughput screening; improved; innovation; insight; novel; novel therapeutics; opioid misuse; opioid therapy; opioid use disorder; pharmacophore; polysubstance use; prescription opioid; prevent; protein complex; response; screening; substance use treatment; virtual; virtual model; virtual screening

Abstract Both human and rodent data showing reduced expression of the small-conductance, calcium- activated potassium channel KCa2.2 (SK2) in the context of morphine and alcohol dependence and withdrawal suggest KCa2 channel activation as a promising therapeutic approach for the treatment of substance use disorders and associated comorbidities. In support of this therapeutic hypothesis, KCa2 channel activators reduce alcohol seeking and intake in rats, while direct injection of the KCa2 channel blocking peptide apamin into the nucleus accumbens, a brain region which plays a crucial role in regulating craving and drug seeking during abstinence, increases alcohol intake in mice. In response to the HEAL Initiative RFA-DA-22-032 Funding Opportunity Announcement, we are here proposing to perform virtual high-throughput-screening with the goal of identifying novel KCa2 activator pharmacophores that are free of the liabilities of the existing unselective benzothiazole-type activators and that could be developed into innovative treatments for opioid use disorders (OUD), a condition that affects more than 3 million Americans. For the implementation of this project, we will draw on our 20 years of experience with the medicinal chemistry of KCa channels. After we initially developed KCa3.1 blockers such as TRAM-34, we later discovered the mixed KCa2/3 activator SKA-31, and the KCa3.1 selective activators SKA-121 and SKA-111. All these compounds, which have been widely used in the field to probe the physiological and pathophysiological roles of KCa channels were designed using classical medicinal chemistry approaches without any structural insight. However, the MacKinnon laboratory recently published the full-length cryo-EM structure of a KCa channel in the closed and two open states and we now have a high-quality structural template available to virtually screen for novel KCa2.2 channel modulators that could be used as pharmacological probes and as leads for the design of drugs for the treatment of OUD. In Aim-1, we will validate our KCa3.1-based KCa2.2 homology model by virtually screening 2000 FDA-approved compounds in two activator binding pockets and experimentally confirm the hits by electrophysiology and mutagenesis. In Aim-2, we will perform a virtual High Throughput Screen (vHTS) of a larger, 130,000-compound library with machine learning (ML) techniques for pose classification and binding affinity prediction. Taken together, these two aims have the potential of 1) identifying a clinically used drug that could be repurposed for OUD and 2) discovering novel KCa2.2 activator pharmacophores that could serve as templates for structure- based-medicinal chemistry optimization aimed at developing OUD treatments with a novel mechanism of action.

摘要 人类和啮齿动物的数据都显示小电导，钙- 吗啡和酒精依赖背景下激活的钾通道KCa2.2(SK2)和 停药提示钾通道激活可作为一种有前途的治疗方法 物质使用障碍及相关的合并症。为了支持这一治疗假说，KCa2 通道激动剂减少大鼠的酒精寻求和摄取，而直接注射钾通道 阻断多肽阿帕明进入伏隔核，这是大脑中发挥关键作用的区域 调节戒断期间的渴求和寻求药物，增加小鼠的酒精摄入量。作为回应 为了宣布Hear Initiative RFA-DA-22-032资助机会，我们在这里提议 进行虚拟高通量筛选，目标是确定新的KCa2激活剂 不受现有非选择性苯并噻唑型活化剂责任的药效团 这可以被开发成阿片类药物使用障碍(OUD)的创新治疗方法，这是一种疾病 这影响了300多万美国人。 为了实施这个项目，我们将利用我们20年来 KCA经络的药物化学。在我们最初开发了像TRAM-34这样的KCa3.1阻滞剂之后， 后来我们发现了KCa3/3混合激活剂SKA-31和KCa3.1选择性激活剂SKA-121 和SKA-111。所有这些化合物都已被广泛应用于该领域的探索 用经典药物设计KCA通道的生理和病理生理学作用 没有任何结构洞察力的化学方法。然而，麦金农实验室最近 发表了KCA通道在封闭和两个开放状态下的全长低温电磁结构，我们 现在有高质量结构模板可用于虚拟筛选新的KCa2.2频道 调节剂，可用作药理探针，并可作为药物设计的先导 OUD的处理。在AIM-1中，我们将通过虚拟验证我们基于KCa3.1的KCa2.2同源模型 在两个活化剂结合口袋中筛选2000种FDA批准的化合物并进行实验 通过电生理学和诱变确认命中。在AIM-2中，我们将执行虚拟兴奋 具有机器学习(ML)的更大的130,000个复合库的吞吐量屏幕(VHTS) 姿势分类和绑定亲和力预测技术。加在一起，这两个目标有 潜在的1)确定一种临床使用的药物，可以重新用于OUD和2) 发现可用作结构模板的新型KCa2.2激活剂药效团- 以药物化学为基础的优化，旨在开发具有新的药物治疗方法 作用机制。